Professor Eugenie Lumbers

Professor Eugenie Lumbers

Professor

School of Biomedical Sciences and Pharmacy (Pharmacy and Experimental Pharmacology)

Career Summary

Biography

ACADEMIC QUALIFICATIONS: MBBS  (Adel, 1965); MD (Adel, 1970); DSc (UNSW, 1986).

CURRENT APPOINTMENT/S: Current positions; Conjoint Professor UNSW 2003-2013; Conjoint Professor University of Queensland, 2009-2011; Professorial appointment; University of Newcastle (continuing). 

HONOURS AND AWARDS: 1972-1974 C.J. Martin Travelling Fellowship (NHMRC); first woman; 1988; awarded a personal chair in physiology at UNSW on basis of research achievements. 1998: Scientia  Professor (first cohort; first woman; for research); 2002 Fellow Australian Academy of Science; 2002:        Life Membership of the Australian Physiological Society; 2002: Centenary Medal of Federation, Australia.. 2011: Fellow of the Royal Society of NSW. 2012: Order of Australia (general division).

         NATIONAL AND INTERNATIONAL PROFILE:  Eugenie Lumbers has a national and international profile since her early discovery of an inactive form of renin (prorenin) that is activated by proteolysis. Lumbers made significant discoveries in adult and fetal cardiovascular physiology on inhibition of the vagal component of the cardiac baroreflex by angiotensin, the fetal cardiovascular effects of cortisol and in her work in fetal cardiovascular physiology and renal function (with particular reference to the renin-angiotensin system). She has studied fetal programming i.e. the impact of maternal renal dysfunction on fetal renal development. She is widely known to a range of medical scientists in the USA and UK. In 2008 she began work on the role(s) of the human intrauterine renin angiotensin system (RAS). She has developed collaborations with Professor Claire Roberts, Gus Dekker (U Adel) and Professor Fiona Broughton Pipkin, Nottingham (U Nottingham) and with Professor Paul Colditz and Dr Barbara Lingwood (UQ), Professor Roger Smith AM (Indigenous renal health) and Professor Rodney Scott (U Newcastle) the  RAS and endometrial cancer.

MAJOR FUNDING SUPPORT: In 1974 Lumbers began work as a Senior lecturer at UNSW; getting her first NHMRC grant in 1975. She continuously held 1 or more NHMRC grants up to and including 2003. Over the same period she had NHF, ARC and AKF support. She was a CI on 3 current NHMRC grants that expired in 2011. She is currently CIC on 4 NHMRC projects 1) 2 commenced in 2012; one finishes at the end of 2014 ; 2) she is CIA on another 2013-2015 and 3)  CIB on one 2014-2016. She has also been awarded research support by University of Newcastle and HMRI.

PUBLICATIONS: 179 publications; 145 papers in refereed journals; 34 other: reviews, book chapters and other writings, co-author of >350 abstracts; Citation report: H-index =32, Citation count: 3864; average citation count 20.2, citation count p.a.84; 3>200,6>100. In 2008, I initiated a new line of research after not working since Feb 2003, my yearly citation count was 74 that year; it rose to 101 in 2013 as my new research effort became productive (Web of science).

Plenary, Keynote and invited talks:

Within Australia University of Sydney, University of Melbourne, Monash University and Adelaide University. Overseas;         USA: University of California (Harbor, San Diego), Cornell University, University of Iowa, The University of Pennsylvania, University of Health Sciences (Portland, Oregon), Downstate Medical Centre, NY, Southwestern University, Dallas, Texas. UK: The University of Cambridge, Oxford University, Southampton University, Nottingham University. Other: Universiti Sains (Malaysia); University of Auckland; Beijing Medical University, Beijing; Astra Pain Control, Stockholm; Harbin First Medical College, Harbin (China); Erasmus Medical College, Rotterdam; University of Southern Denmark, Odense. Invited Speaker; Since 2007 I have had 6 national/international invitations to speak with costs partly defrayed (2 in 2013).

COMMUNITY ENGAGEMENT: Scientists in Schools (CSIRO); community groups, media on animal based research and on medical research.

PEER REVIEW AND DISCIPLINE INVOLVEMENT:

Editorial boards; refere(ed) for Circulation Research, MJA, CEPP, AJP, J Physiol,, J Dev Physiol, Ped Res, Anat Rec Hypertension, Placenta, Reproduction and Fertility. PLos (one), DOHAD J. Acta Physiologic Scand.

Research Expertise
Eugenie Lumbers has a national and international profile since her discovery of prorenin. Lumbers made significant discoveries in adult and fetal cardiovascular physiology on inhibition of the vagal component of the cardiac baroreflex by angiotensin, the fetal cardiovascular effects of cortisol and in her work in fetal cardiovascular physiology and renal function (with particular reference to the renin-angiotensin system). She has studied fetal programming i.e. the impact of maternal renal dysfunction on fetal renal development. She is widely known to a range of medical scientists in the USA and UK. In 2008 she began work on the role(s) of the human intrauterine renin angiotensin system (RAS). She has developed collaborations with Professor Claire Roberts, Gus Dekker (U Adel) and Professor Fiona Broughton Pipkin, Nottingham (U Nottingham) and with Professor Paul Colditz and Dr Barbara Lingwood (UQ), Professor Roger Smith AM (Indigenous renal health) and Professor Rodney Scott (U Newcastle) the RAS and endometrial cancer and Professor Caroline Blackwell (inflammation and chronic disease in Indigenous Australians. • NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL • Member of Regional Grants Interviewing Committees which visited Melbourne (1979, 1982, 1984, 1985, 1989, 1994, 1995 and 1996) and Brisbane (1988). • In 1989, I spoke at public meetings on the NH&MRC case for funds. • Member of the NHMRC Quinquennial Review Committee which reviewed the Howard Florey Institute, Melbourne (1989). • Appreciator for NHMRC Triennial Review (1990). Member of the committee that reviewed NH&MRC for the Minister for Community Services and Health (1990). • Assessor for project grant applications (1980 - present). • Member of NH&MRC Careers and Awards Committee (1989 - 1993). • NHMRC representative on the Appointment and Promotions Committee for Baker Medical Research Institute (1991 - present). • Member of Assigner’s Panel (1991, 1994 -1998). • Member of the NHMRC Quinquennial Review Committee which reviewed the Howard Florey (1991) and the Baker Medical Research Institute (1992). • Member of NHMRC Fellowship Committee (1993). • Chair, NHMRC RGIC, Melbourne (1994 - 1996). • Member of NHMRC Grants Committee (1994 - 1996). • Member of NHMRC Medical Research Council (1994 - 1996). • Regional Chair, NHMRC, site visit NRCET (1995). • Member of Quinnquenial Review Committee for Howard Florey Institute (1997). • Member of NHMRC Discipline Panel (2001-2002). • Member NHMRC GRP3b (2007). NATIONAL HEART FOUNDATION • Assessor for project grant applications and program grants (1984 - 1995). • Member of NSW National Heart Foundation Scientific Advisory Committee (1983 - present). • Member of the National Heart Foundation Interviewing Committee which visited Perth and Adelaide (1985), Adelaide (1986), Brisbane and Adelaide (1986), Melbourne and Adelaide (1987). • Member of National Heart Fellowships Committee (1988 - 1989). • Chair, NHF Regional Grants Committee (1992). • National Cardiovascular Advisory Committee member (1997-2002). • Presiding member of Scientific Advisory Committee of NSW division of NHF (1997- 2002). • AUSTRALIAN RESEARCH COUNCIL • ARC Biological Sciences Discipline Panel (1999 - 2000). NEW ZEALAND HEALTH RESEARCH COUNCIL • Project grants committee (2002, 2005)

Teaching Expertise
UNDERGRADUATE TEACHING: Medical and Science students in physiology and pharmacology from 1974-2003. Lecturer to medical or science students at U Newcastle and UNSW. MENTORING AND RESEARCH TRAINING: ERL has successfully supervised 23 honors students and 18 PhD students. Currently she is cosupervising 1 PhD student and 1 honors student and mentoring 1 BMedSci student. AUSTRALIAN MEDICAL COUNCIL • Member of teams that accredited medical courses at the following universities: Flinders University (old course), Flinders University (new course), University of Queensland, James Cook University, University of Tasmania (2005). • Member, AMC Accreditation Committee (1997 - 1999). OTHERS • Course Accreditation Committees to Canberra CAE (1988 & 1989). • Medical Appointment Advisory Committee for the Royal Hospital for Women (1985 - 1989). • PhD Advisory Committee, School of Applied Science, University of Canberra (1989). • Course Accreditation Committee for University of Canberra Bachelor of Nursing course, Canberra (1991). • Review Faculty of Science UTS (1995). • Reviewer for Dr J Faber's program grant at the University of Health Sciences, Portland, Oregon. • Member of Management Committee for CRC (Biopharmaceuticals) from 1992 - 2000. • Member of Committee that reviewed the Department of Obstetrics and Gynecology. The University of Sydney (1993). • Prime Minister's Advisory Committee for Women in Science, Engineering and Technology (1993). • Member of the Academy of Science National Committee for Physiology (1993 - 1999). • Member of the Australian Perinatal Society Programme Resource Committee (1993 - 1995). • Member of WISET Advisory Group (1994 - 1995). • Member of New Zealand Health Research Council to visit Gluckman Programme, University of Auckland (1994), member of Physiology Assessment Committee (1994). • Research Advisory Committee, Prince of Wales Children Research Foundation (1990- 2002). • Member of the Research and Executive Committee of the Australian Society for Medical Research (ASMR) Research Fund (1994- 2002). • Consultant DEET & DEEWR 2006, 2007, 2008. • I have assisted the Academy of Science in appraisal of scholarships and grants

Administrative Expertise
Head of School of physiology and Pharmacology UNSW 1991-1999 Other General • Member of the UNSW Animal Breeding and Holding Unit Management Committee (1981 - 1983) • Chairman of the UNSW Animal Breeding and Holding Unit Management Committee (1984 - 1987). • Member of the Advisory Committee for the UNSW Animal Breeding and Holding Unit (1987). • Member of the UNSW Committee for the Use of Animals in Research and Teaching (1983 - 1987). • Member of Selection Committees for Appointment of Academic Staff to the Faculty of Military Studies, Medicine, Professional Studies, and others (1984 - 1987). • Elected to the UNSW Council (1986 - 1996). • Member of Buildings and Equipment Committee of UNSW Council (1986 - 1990). • Member of the Academic Committee of UNSW Council (1988 - 1990). • Presiding Member of Women Academic's Group (1989). • Elected as representative of the Academic Staff to the UNSW Council (1990 - 1991; 1994-1996). • Presiding Member of Student Affairs Committee of UNSW Council (1990 - 1996). • Member of EEO & Advisory Committee of Council (1989 - 1992). • Member of Committee of the Review Committee the School of Community Medicine, UNSW (May, 1993). • Chair UNSW Child-Care Support Fund (from inception until 2002). • Elected Member of Academic Board (1994 - 1996). • Elected Member of the Academic Board, May 2001-June 2002. • Member of Research Committee, Academic Board , UNSW, February, 2002- June 2002. Faculty • Member of the Faculty of Medicine Promotions Committee (1987 - 1995). • Member of the Executive Committee of the Faculty of Medicine (1980 - 1985; 1991). • Year 3 New Curriculum Subcommittee for the 6 year medical course (1987). • Member of Higher Degree Committee (1987). • Member of Faculty of Medicine Academic Promotions to Professor and Associate Professor Committee (1991 onwards). • Member of Faculty of Medicine Honours and Postgraduate Course Committee (1991- 1997). • Member of Faculty of Medicine Research Advisory Committee (1991 - present). • Member of Faculty of Medicine Dean's Advisory Committee (1991 - 1998). • Representative for UNSW Faculty of Medicine in International Medical College meeting, Malaysia (1992). • Postgraduate Coordinator for the School of Physiology and Pharmacology (1992 - 1995). • Member of Faculty Research Committee (2001-2002). • Research Coordinator School of Medical Sciences (2002). Boards • National Heart Foundation, NSW Division (1997-2002) • Heart Research Institute (representing the NHF) • Elected Member of ANZCCART Board (1993 - 1995) • Board member of ANZCCART as representative of the ARC (1999-2000)

Collaborations
Current collaborations with Professor Claire Roberts, Gus Dekker (U Adel) and Professor Fiona Broughton Pipkin, Nottingham (U Nottingham) and with Professor Paul Colditz and Dr Barbara Lingwood (UQ), Professor Roger Smith AM (Indigenous renal health) and Professor Rodney Scott (U Newcastle) the RAS and endometrial cancer, Professoer caroline Balckwell (inflammation and cardiovascular and renal disease). Professor Brina Morris (U Syd) RAS.

Qualifications

  • Doctor of Science, University of New South Wales
  • Bachelor of Medicine, Bachelor of Surgery, University of Adelaide
  • Doctor of Medicine, University of Adelaide

Keywords

  • cardiovascular
  • fetal
  • fetal cardiovascular and renal phsyiology
  • fetal origins of adult disease
  • hypertension
  • maternal
  • maternal physiology
  • medical pharmacology
  • medical physiology
  • neonatal
  • placenta
  • renal
  • renin angiotensin system
  • reproductive

Fields of Research

Code Description Percentage
111499 Paediatrics and Reproductive Medicine not elsewhere classified 30
111699 Medical Physiology not elsewhere classified 40
111501 Basic Pharmacology 30

Professional Experience

UON Appointment

Title Organisation / Department
Professor University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia

Academic appointment

Dates Title Organisation / Department
1/01/2009 -  Professor The University of Queensland
UQ Centre for Clinical Research (UQCCR)
Australia
1/01/2009 -  Professor University of Newcastle
School of Biomedical Sciences
Australia
1/01/2007 - 1/12/2008 Professor University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia
1/01/2006 -  Consultant The University of Adelaide
School of Women and Child Health
Australia
1/02/2003 -  Emeritus Scientia Professor The University of New South Wales
Australia
1/01/1999 - 1/02/2003 Scientia Professor The University of New South Wales
School of Physiology and Pharmacology
Australia
1/01/1988 - 1/12/1999 Professor The University of New South Wales
School of Physiology and Pharmacology
Australia
1/01/1980 - 1/12/1988 Associate Professor The University of New South Wales
School of Physiology and Pharmacology
Australia
1/01/1980 - 1/07/1980 Visiting Professor Univeristy of California San Fancisco
United States
1/01/1974 - 1/12/1979 Senior Lecturer The University of New South Wales
School of Physiology and Pharmacology
Australia
1/01/1972 - 1/12/1973 CJ Martin Fellow Oxford University, UK
Nuffield Institute for Medical Research
United Kingdom
1/01/1970 - 1/12/1971 NHMRC Senior Research Officer The University of Adelaide
Physiology
Australia
1/01/1966 - 1/12/1969 Postgraduate Medical Scholar The University of Adelaide
National Health and Medical Research Council (NHMRC)
Australia
Edit

Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Book (1 outputs)

Year Citation Altmetrics Link
2000 Lumbers ER, The renal circulation in pregnancy (2000)

The increased RBF that occurs in pregnancy is due to equivalent relaxation of afferent and efferent arterioles so that GPF is increased. Intracapillary glomerular hydrostatic pres... [more]

The increased RBF that occurs in pregnancy is due to equivalent relaxation of afferent and efferent arterioles so that GPF is increased. Intracapillary glomerular hydrostatic pressure (Pgc) and the ultrafiltration coefficient (Kf) are unchanged. The increase in GPF is responsible for the increase in GFR. The mechanisms responsible for these changes in glomerular hemodynamics are unknown. To some extent they occur in the pseudopregnant rat; therefore, in that species it is likely that these changes in RBF and GFR are independent of the presence of the conceptus. A number of possible endocrine/paracrine factors may be responsible. NO is a likely candidate. Blockade of NO production normalizes RBF and GFR to nonpregnant levels and produces changes in glomerular structure similar to those seen in preeclampsia. © 2000.

Citations Scopus - 2
Co-authors E Lumbers

Chapter (1 outputs)

Year Citation Altmetrics Link
2013 Pringle KG, Lumbers ER, 'The placental renin angiotensin system', The Placenta: Development, Function and Diseases, Nova Science, New York 261-288 (2013) [B1]
Co-authors E Lumbers, Kirsty Pringle

Journal article (206 outputs)

Year Citation Altmetrics Link
2017 Pringle KG, Zakar T, Lumbers ER, 'The intrauterine renin-angiotensin system: Sex-specific effects on the prevalence of spontaneous preterm birth.', Clin Exp Pharmacol Physiol, 44 605-610 (2017)
DOI 10.1111/1440-1681.12734
Co-authors E Lumbers, Kirsty Pringle
2017 Delforce SJ, Lumbers ER, Corbisier de Meaultsart C, Wang Y, Proietto A, Otton G, et al., 'Expression of renin-angiotensin system (RAS) components in endometrial cancer.', Endocr Connect, 6 9-19 (2017)
DOI 10.1530/EC-16-0082
Co-authors Kirsty Pringle, Rodney Scott, E Lumbers, Nikki Verrills
2017 Mah B, Weatherall L, Burrows J, Blackwell CC, Gwynn J, Wadhwa P, et al., 'Post-traumatic stress disorder symptoms in pregnant Australian Indigenous women residing in rural and remote New South Wales: A cross-sectional descriptive study.', Aust N Z J Obstet Gynaecol, (2017)
DOI 10.1111/ajo.12618
Co-authors Julie Burrows, Josephine Gwynn, Kym Rae, Roger Smith, E Lumbers
2017 Delforce SJ, Lumbers ER, Pringle KG, 'Regulation of the prorenin - angiotensin system by oxygen and miRNAs; parallels between placentation and tumour development?', Placenta, 56 27-33 (2017)
DOI 10.1016/j.placenta.2017.03.007
Co-authors Kirsty Pringle, E Lumbers
2016 Eiby YA, Shrimpton NY, Wright IMR, Lumbers ER, Colditz PB, Duncombe GJ, Lingwood BE, 'Inotropes do not increase cardiac output or cerebral blood flow in preterm piglets', Pediatric Research, 80 870-879 (2016) [C1]

Copyright © 2016 International Pediatric Research Foundation, Inc. Background:The preterm newborn is at high risk of developing cardiovascular compromise during the first day of ... [more]

Copyright © 2016 International Pediatric Research Foundation, Inc. Background:The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model.Methods:Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10 µg/kg/h), and high (20 µg/kg/h) dose infusions.Results:At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or dobutamine administration was less than in term piglets. In both preterm and term piglets, cardiac output and cerebral blood flow were unaltered by either inotrope.Conclusion:In order to provide better cardiovascular support, it may be necessary to develop treatments that target receptors with a more mature profile than adrenoceptors in the preterm newborn.

DOI 10.1038/pr.2016.156
Citations Scopus - 1
Co-authors E Lumbers, Ian Wright
2016 Ashman AM, Collins CE, Weatherall L, Brown LJ, Rollo ME, Clausen D, et al., 'A cohort of Indigenous Australian women and their children through pregnancy and beyond: The Gomeroi gaaynggal study', Journal of Developmental Origins of Health and Disease, 7 357-368 (2016) [C1]

© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016. Indigenous Australians have high rates of chronic diseases, the c... [more]

© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016. Indigenous Australians have high rates of chronic diseases, the causes of which are complex and include social and environmental determinants. Early experiences in utero may also predispose to later-life disease development. The Gomeroi gaaynggal study was established to explore intrauterine origins of renal disease, diabetes and growth in order to inform the development of health programmes for Indigenous Australian women and children. Pregnant women are recruited from antenatal clinics in Tamworth, Newcastle and Walgett, New South Wales, Australia, by Indigenous research assistants. Measures are collected at three time points in pregnancy and from women and their children at up to eight time points in the child's first 5 years. Measures of fetal renal development and function include ultrasound and biochemical biomarkers. Dietary intake, infant feeding and anthropometric measurements are collected. Standardized procedures and validated tools are used where available. Since 2010 the study has recruited over 230 women, and retained 66 postpartum. Recruitment is ongoing, and Gomeroi gaaynggal is currently the largest Indigenous pregnancy-through-early-childhood cohort internationally. Baseline median gestational age was 39.1 weeks (31.5-43.2, n=110), median birth weight was 3180 g (910-5430 g, n=110). Over one third (39.3%) of infants were admitted to special care or neonatal nursery. Nearly half of mothers (47.5%) reported tobacco smoking during pregnancy. Results of the study will contribute to knowledge about origins of chronic disease in Indigenous Australians and nutrition and growth of women and their offspring during pregnancy and postpartum. Study strengths include employment and capacity-building of Indigenous staff and the complementary ArtsHealth programme.

DOI 10.1017/S204017441600009X
Citations Scopus - 1Web of Science - 2
Co-authors E Lumbers, Caroline Blackwell, Leanne Brown, Roger Smith, Clare Collins, Kirsty Pringle, Megan Rollo, John Attia, Kym Rae
2016 Grimson S, Cox AJ, Pringle KG, Burns C, Lumbers ER, Blackwell CC, Scott RJ, 'The prevalence of unique SNPs in the renin-angiotensin system highlights the need for pharmacogenetics in Indigenous Australians', Clinical and Experimental Pharmacology and Physiology, 43 157-160 (2016) [C1]

© 2016 John Wiley & Sons Australia, Ltd. Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared... [more]

© 2016 John Wiley & Sons Australia, Ltd. Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049); AGT G+174A (rs4762); Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186); angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292); renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations; 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non-Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous individuals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines.

DOI 10.1111/1440-1681.12525
Co-authors Kirsty Pringle, Rodney Scott, Caroline Blackwell, E Lumbers
2016 Delforce SJ, Wang Y, Van-Aalst ME, Corbisier De Meaultsart C, Morris BJ, Broughton-Pipkin F, et al., 'Effect of oxygen on the expression of renin-angiotensin system components in a human trophoblast cell line', Placenta, 37 1-6 (2016) [C1]

© 2015 Elsevier Ltd. All rights reserved. During the first trimester, normal placental development occurs in a low oxygen environment that is known to stimulate angiogenesis via ... [more]

© 2015 Elsevier Ltd. All rights reserved. During the first trimester, normal placental development occurs in a low oxygen environment that is known to stimulate angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Expression of the placental renin-angiotensin system (RAS) is highest in early pregnancy. While the RAS and oxygen both stimulate angiogenesis, how they interact within the placenta is unknown. We postulated that low oxygen increases expression of the proangiogenic RAS pathway and that this is associated with increased VEGF in a first trimester human trophoblast cell line (HTR-8/SVneo). HTR-8/SVneo cells were cultured in one of three oxygen tensions (1%, 5% and 20%). RAS and VEGF mRNA expression were determined by qPCR. Prorenin, angiotensin converting enzyme (ACE) and VEGF protein levels in the supernatant, as well as prorenin and ACE in cell lysates, were measured using ELISAs. Low oxygen significantly increased the expression of both angiotensin II type 1 receptor (AGTR1) and VEGF (both P < 0.05). There was a positive correlation between AGTR1 and VEGF expression at low oxygen (r = 0.64, P < 0.005). Corresponding increases in VEGF protein were observed with low oxygen (P < 0.05). Despite no change in ACE1 mRNA expression, ACE levels in the supernatant increased with low oxygen (1% and 5%, P < 0.05). Expression of other RAS components did not change. Low oxygen increased AGTR1 and VEGF expression, as well as ACE and VEGF protein levels, suggesting that the proangiogenic RAS pathway is activated. This highlights a potential role for the placental RAS in mediating the proangiogenic effects of low oxygen in placental development.

DOI 10.1016/j.placenta.2015.11.011
Citations Scopus - 2Web of Science - 2
Co-authors Kirsty Pringle, E Lumbers
2016 Pringle KG, Delforce SJ, Wang Y, Ashton KA, Proietto A, Otton G, et al., 'Renin-angiotensin system gene polymorphisms and endometrial cancer', ENDOCRINE CONNECTIONS, 5 128-135 (2016) [C1]
DOI 10.1530/EC-15-0112
Citations Web of Science - 1
Co-authors E Lumbers, Kirsty Pringle, Rodney Scott, Caroline Blackwell
2015 Wang Y, Lumbers ER, Sykes SD, Pringle KG, 'Regulation of the renin-angiotensin system pathways in the human decidua', Reproductive Sciences, 22 865-872 (2015) [C1]

© 2014 The Author(s). Pregnancy outcome is influenced, in part, by the sex of the fetus. Decidual renin messenger RNA (REN) abundance is greater in women carrying a female fetus ... [more]

© 2014 The Author(s). Pregnancy outcome is influenced, in part, by the sex of the fetus. Decidual renin messenger RNA (REN) abundance is greater in women carrying a female fetus than a male fetus. Here, we explore whether the sex of the fetus also influences the regulation of decidual RAS expression with a known stimulator of renal renin and cyclic adenosine monophosphate (cAMP). Cyclic adenosine monophosphate had no affect on decidual REN expression, since REN abundance was still greater in decidual explants from women carrying a female fetus than a male fetus after cAMP treatment. Cyclic adenosine monophosphate decreased prorenin levels in the supernatant if the fetus was female (ie, prorenin levels were no longer sexually dimorphic) and altered the fetal sex-specific differences in other RAS genes seen in vitro. Therefore, fetal sex influences the decidual renin-angiotensin system response to cAMP. This may be related to the presence of fetal cells in the maternal decidua.

DOI 10.1177/1933719114565029
Citations Scopus - 2Web of Science - 2
Co-authors Kirsty Pringle, E Lumbers
2015 Pringle KG, Conquest A, Mitchell C, Zakar T, Lumbers ER, 'Effects of Fetal Sex on Expression of the (Pro)renin Receptor and Genes Influenced by its Interaction With Prorenin in Human Amnion', Reproductive Sciences, 22 750-757 (2015) [C1]

© The Author(s) 2014. Males are more likely to be born preterm than females. The causes are unknown, but it is suggested that intrauterine tissues regulate fetal growth and survi... [more]

© The Author(s) 2014. Males are more likely to be born preterm than females. The causes are unknown, but it is suggested that intrauterine tissues regulate fetal growth and survival in a sex-specific manner. We postulated that prorenin binding to its prorenin/renin receptor receptor (ATP6AP2) would act in a fetal sex-specific manner in human amnion to regulate the expression of promyelocytic zinc finger, a negative regulator of ATP6AP2 expression as well as 2 pathways that might influence the onset of labor, namely transforming growth factor ß1 (TGFB1) and prostaglandin endoperoxide synthase 2 (PTGS2). Our findings demonstrate that there are strong interactions between prorenin, ATP6AP2, and TGFB1 and that this system has a greater capacity in female amnion to stimulate profibrotic pathways, thus maintaining the integrity of the fetal membranes. In contrast, glucocorticoids or other factors independent of the prorenin/prorenin receptor pathway may be important regulators of PTGS2 in human pregnancy.

DOI 10.1177/1933719114561555
Citations Scopus - 1Web of Science - 1
Co-authors Kirsty Pringle, E Lumbers
2015 Standen P, Sferruzzi-Perri AN, Taylor R, Heinemann G, Zhang JV, Highet AR, et al., 'Maternal insulin-like growth factor 1 and 2 differentially affect the renin-angiotensin system during pregnancy in the guinea pig', GROWTH HORMONE & IGF RESEARCH, 25 141-147 (2015) [C1]
DOI 10.1016/j.ghir.2015.02.001
Citations Scopus - 1
Co-authors E Lumbers, Kirsty Pringle
2015 White AJR, Cheruvu SC, Sarris M, Liyanage SS, Lumbers E, Chui J, et al., 'Expression of classical components of the renin-angiotensin system in the human eye', JRAAS - Journal of the Renin-Angiotensin-Aldosterone System, 16 59-66 (2015) [C1]

© The Author(s) 2014. Purpose: The purpose of this study was to determine the relative expression of clinically-relevant components of the renin-angiotensin system (RAS) in the a... [more]

© The Author(s) 2014. Purpose: The purpose of this study was to determine the relative expression of clinically-relevant components of the renin-angiotensin system (RAS) in the adult human eye. Methods: We obtained 14 post-mortem enucleated human eyes from patients whom had no history of inflammatory ocular disease nor pre-mortem ocular infection. We determined the gene expression for prorenin, renin, prorenin receptor, angiotensin-converting enzyme, angiotensinogen and angiotensin II Type 1 receptor, on tissue sections and in cultured human primary retinal pigment epithelial and iris pigment epithelial (RPE/IPE) cell lines, using both qualitative and quantitative reverse transcription polymerase chain reaction (RT-PCR). Protein expression was studied using indirect immunofluorescence (IF). Results: Almost all components of the classical RAS were found at high levels, at both the transcript and protein level, in the eyes' uvea and retina; and at lower levels in the cornea, conjunctiva and sclera. There was a much lower level of expression in the reference cultured RPE/IPE cells lines. Conclusion: This study describes the distribution of RAS in the normal adult human eye and demonstrates the existence of an independent ocular RAS, with uveal and retinal tissues showing the highest expression of RAS components. These preliminary findings provide scope for examination of additional components of this system in the human eye, as well as possible differential expression under pathological conditions.

DOI 10.1177/1470320314549791
Citations Scopus - 7
Co-authors E Lumbers
2015 Pringle KG, Wang Y, Lumbers ER, 'The synthesis, secretion and uptake of prorenin in human amnion.', Physiological reports, 3 (2015) [C1]
Citations Scopus - 1
Co-authors E Lumbers, Kirsty Pringle
2015 Sykes SD, Mitchell C, Pringle KG, Wang Y, Zakar T, Lumbers ER, 'Methylation of promoter regions of genes of the human intrauterine renin angiotensin system and their expression', International Journal of Endocrinology, 2015 (2015) [C1]

© 2015 Shane D. Sykes et al. The intrauterine renin angiotensin system (RAS) is implicated in placentation and labour onset. Here we investigate whether promoter methylation of R... [more]

© 2015 Shane D. Sykes et al. The intrauterine renin angiotensin system (RAS) is implicated in placentation and labour onset. Here we investigate whether promoter methylation of RAS genes changes with gestation or labour and if it affects gene expression. Early gestation amnion and placenta were studied, as were term amnion, decidua, and placenta collec ted before labour (at elective caesarean section) or after spontaneous labour and delivery. The expression and degree of methylation of the prorenin receptor (ATP6AP2), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and two proteases that can activate prorenin (kallikrein, KLK1, and cathepsin D, CTSD) were measured by qPCR and a DNA methylation array. There was no effect of gestation or labour on the methylation of RAS genes and CTSD. Amnion and decidua displayed strong correlations between the percent hypermethylation of RAS genes and CTSD, suggestive of global methylation. There were no correlations between the degree of methylation and mRNA abundance of any genes studied. KLK1 was the most methylated gene and the proportion of hypermethylated KLK1 alleles was lower in placenta than decidua. The presence of intermediate methylated alleles of KLK1 in early gestation placenta and in amnion after labour suggests that KLK1 methylation is uniquely dynamic in these tissues.

DOI 10.1155/2015/459818
Citations Scopus - 1
Co-authors E Lumbers, Kirsty Pringle
2015 Pringle KG, Weatherall L, Corbisier de Meaultsart C, Keogh L, Sands S, Blackwell C, et al., 'The Gomeroi Gaaynggal Cohort: A Preliminary Study of the Maternal Determinants of Pregnancy Outcomes in Indigenous Australian Women', Journal of Pregnancy and Child Health, 3 (2015) [C1]
DOI 10.4172/2376-127X.1000211
Co-authors Sharron Hall, E Lumbers, Roger Smith, Caroline Blackwell, Clare Collins, Kirsty Pringle, Kym Rae
2015 Pringle KG, Rae K, Weatherall L, Hall S, Burns C, Smith R, et al., 'Effects of maternal inflammation and exposure to cigarette smoke on birth weight and delivery of preterm babies in a cohort of Indigenous Australian women', Frontiers in Immunology, 6 (2015) [C1]

© 2015 Pringle, Rae, Weatherall, Hall, Burns, Smith, Lumbers and Blackwell. Sudden infant death syndrome (SIDS), neonatal deaths, and deaths from infection are higher among Indig... [more]

© 2015 Pringle, Rae, Weatherall, Hall, Burns, Smith, Lumbers and Blackwell. Sudden infant death syndrome (SIDS), neonatal deaths, and deaths from infection are higher among Indigenous Australians. This study aimed to determine the effects of inflammatory responses and exposure to cigarette smoke, two important factors associated with sudden death in infancy, on preterm birth, and birth weight in a cohort of Indigenous mothers. Indigenous Australian women (n = 131) were recruited as part of a longitudinal study while attending antenatal care clinics during pregnancy; blood samples were collected up to three times in pregnancy. Serum cotinine, indicating exposure to cigarette smoke, was detected in 50.4% of mothers. Compared with non-Indigenous women, the cohort had 10 times the prevalence of antibodies to Helicobacter pylori (33 vs. 3%). Levels of immunoglobulin G, antibodies to H. pylori, and C-reactive protein (CRP) were all inversely correlated with gestational age (P < 0.05). CRP levels were positively associated with maternal body mass index (BMI; ¿ = 0.449, P = 0.001). The effects of cigarette smoke (cotinine) and inflammation (CRP) were assessed in relation to risk factors for SIDS: gestational age at delivery and birth weight. Serum cotinine levels were negatively associated with birth weight (¿ = -0.37, P < 0.001), this correlation held true for both male (¿ = -0.39, P = 0.002) and female (¿ = -0.30, P = 0.017) infants. Cotinine was negatively associated with gestational age at delivery (¿ = -0.199, P = 0.023). When assessed by fetal sex, this was significant only for males (¿ = -0.327, P = 0.011). CRP was negatively associated with gestational age at delivery for female infants (¿ = -0.46, P < 0.001). In contrast, maternal BMI was significantly correlated with birth weight. These data highlight the importance of putting programs in place to reduce cigarette smoke exposure in pregnancy and to treat women with chronic infections such as H. pylori to improve pregnancy outcomes and decrease risk factors for sudden death in infancy.

DOI 10.3389/fimmu.2015.00089
Citations Scopus - 3Web of Science - 1
Co-authors E Lumbers, Sharron Hall, Roger Smith, Caroline Blackwell, Kirsty Pringle, Kym Rae
2015 Lumbers ER, Wang Y, Delforce SJ, Corbisier de Meaultsart C, Logan PC, Mitchell MD, Pringle KG, 'Decidualisation of human endometrial stromal cells is associated with increased expression and secretion of prorenin', Reproductive Biology and Endocrinology, 13 (2015) [C1]

© 2015 Lumbers et al. Background: In pregnancy, the decidualised endometrium expresses high levels of prorenin and other genes of the renin-angiotensin system (RAS) pathway. In t... [more]

© 2015 Lumbers et al. Background: In pregnancy, the decidualised endometrium expresses high levels of prorenin and other genes of the renin-angiotensin system (RAS) pathway. In this study we aimed to determined if the RAS was present in endometrial stromal cells and if decidualisation upregulated the expression of prorenin, the prorenin receptor ((P)RR) and associated RAS pathways. Immortalised human endometrial stromal cells (HESCs) can be stimulated to decidualise by combined treatment with medroxyprogesterone acetate (MPA), 17ß-estradiol (E 2 ) and cAMP (MPA-mix) or with 5-aza-2'-deoxycytidine (AZA), a global demethylating agent. Methods: HESCs were incubated for 10days with one of the following treatments: vehicle, MPA-mix, a combination of medroxyprogesterone acetate (MPA) and estradiol-17ß alone, or AZA. Messenger RNA abundance and protein levels of prorenin (REN), the (P)RR (ATP6AP2), angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), vascular endothelial growth factor (VEGF), and plasminogen activator inhibitor-1 (PAI-1) were measured by real-time PCR and ELISA's, respectively. Promyelocytic zinc finger (PLZF) and phospho-inositol-3 kinase (PIK3R1) mRNA abundances were also measured. Results: HESCs expressed the prorenin receptor (ATP6AP2), REN, AGT, ACE and low levels of AGTR1. MPA-mix and AZA stimulated expression of REN. Prorenin protein secretion was increased in MPA-mix treated HESCs. E 2 + MPA had no effect on any RAS genes. MPA-mix treatment was associated with increased VEGF (VEGFA) and PAI-1 (SERPINE1) mRNA and VEGF protein. Conclusions: An endometrial prorenin receptor/renin angiotensin system is activated by decidualisation. Since (P)RR is abundant, the increase in prorenin secretion could have stimulated VEGF A and SERPINE1 expression via Ang II, as both ACE and AGTR1 are present, or by Ang II independent pathways. Activation of the RAS in human endometrium with decidualisation, through stimulation of VEGF expression and secretion, could be critical in establishing an adequate blood supply to the developing maternal placental vascular bed.

DOI 10.1186/s12958-015-0127-8
Citations Scopus - 2Web of Science - 3
Co-authors E Lumbers, Kirsty Pringle
2015 Kim E, Lingwood B, Eiby Y, Lumbers E, Boyce A, Gibson K, 'Expression of genes of the cardiac and renal renin¿angiotensin systems in preterm piglets: Is this system a suitable target for therapeutic intervention?', Therapeutic Advances in Cardiovascular Disease, 9 285-296 (2015) [C1]

The newborn circulating, cardiac and renal renin¿angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal ... [more]

The newborn circulating, cardiac and renal renin¿angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets. Methods: Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT 1 R) and angiotensin type 2 receptor (AT 2 R). Results: All the genes studied were expressed in the kidney; neither renin nor AT 2 R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT 1 R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT 2 R mRNA abundance was highest in GC treated preterm piglets, and the AT 1 R/AT 2 R ratio was increased at term. Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT 1 R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs. © 2015, SAGE Publications. All rights reserved.

DOI 10.1177/1753944715578615
Citations Scopus - 1
Co-authors E Lumbers
2015 Pringle KG, Sykes SD, Lumbers ER, 'Circulating and intrarenal renin-angiotensin systems in healthy men and nonpregnant women.', Physiol Rep, 3 (2015) [C1]
DOI 10.14814/phy2.12586
Citations Scopus - 1
Co-authors Kirsty Pringle, E Lumbers
2014 Sykes SD, Pringle KG, Zhou A, Dekker GA, Roberts CT, Lumbers ER, SCOPE Consortium, 'The balance between human maternal plasma angiotensin II and angiotensin 1-7 levels in early gestation pregnancy is influenced by fetal sex.', J Renin Angiotensin Aldosterone Syst, 15 523-531 (2014) [C1]
DOI 10.1177/1470320313477174
Citations Scopus - 1
Co-authors Kirsty Pringle, E Lumbers
2014 Kandasamy Y, Smith R, Lumbers ER, Rudd D, 'Nephrin - a biomarker of early glomerular injury.', Biomarker Research, 2 1-8 (2014) [C1]
Co-authors Roger Smith, E Lumbers
2014 Kim MY, Eiby YA, Lumbers ER, Wright LL, Gibson KJ, Barnett AC, Lingwood BE, 'Effects of glucocorticoid exposure on growth and structural maturation of the heart of the preterm piglet', PLoS ONE, 9 (2014) [C1]

Inadequate maintenance of systemic blood flow in neonates following preterm birth is associated with increased morbidity and mortality, and may be due in part to structural immatu... [more]

Inadequate maintenance of systemic blood flow in neonates following preterm birth is associated with increased morbidity and mortality, and may be due in part to structural immaturity of the myocardium. Maternal glucocorticoid administration is associated with improved cardiovascular function, and possibly promotes structural maturation of the myocardium. This study assessed the structural maturity of the myocardium in male and female preterm and term piglets, and preterm piglets exposed to a regimen of maternal glucocorticoids as used clinically. In preterm, term and glucocorticoid exposed preterm piglets cardiomyocyte maturity was examined by measuring the proportion of binucleated myocytes and the volumes of single living ventricular cardiomyocytes with fluorescence microscopy. Ventricular apoptosis and proliferation were measured by immunohistochemistry. Preterm piglet hearts had fewer binucleated myocytes, smaller myocytes, and more proliferative and fewer apoptotic nuclei than term hearts. Maternal glucocorticoid treatment resulted in increased binucleation with no increase in myocyte volume, and levels of proliferation and apoptosis that were more similar to the term heart. Atrial weights were increased and in female piglets there was an increase in the ratio of left to right ventricular weight. The observed changes in atrial mass and myocyte structural maturation correlated with changes in cardiac function of isolated hearts of littermates. In conclusion, the association between increased myocardial maturation following glucocorticoid exposure, improved cardiac function in littermates, and clinical improvement in human neonatal cardiac function exposed to antenatal glucocorticoids, suggests that glucocorticoid exposure contributes to improved cardiov ascular function in preterm infants by promoting myocardial structural maturity. © 2014 Kim et al.

DOI 10.1371/journal.pone.0093407
Citations Scopus - 11Web of Science - 8
Co-authors E Lumbers
2014 Kim MY, Finch AM, Lumbers ER, Boyce AC, Gibson KJ, Eiby YA, Lingwood BE, 'Expression of adrenoceptor subtypes in preterm piglet heart is different to term heart', PLoS ONE, 9 (2014) [C1]

Preterm delivery increases the risk of inadequate systemic blood flow and hypotension, and many preterm infants fail to respond to conventional inotrope treatments. If the profile... [more]

Preterm delivery increases the risk of inadequate systemic blood flow and hypotension, and many preterm infants fail to respond to conventional inotrope treatments. If the profile of cardiac adrenoceptor subtypes in the preterm neonate is different to that at term this may contribute to these clinical problems. This study measured mRNA expression of ß1, ß2, a 1A , a 2A and a 2B -adrenoceptor subtypes by real time PCR in term (113d), preterm (91d) and preterm piglets (91d) exposed to maternal glucocorticoid treatment. Abundance of ß-adrenoceptor binding sites in the left ventricle was measured using saturation binding assays. Relative abundance of ß 1 -adrenoceptor mRNA in untreated preterm hearts was ~50% of term abundance in both left and right ventricles (P > 0.001). Trends in receptor binding site density measurements supported this observation (P = 0.07). Glucocorticoid exposure increased ß1-adrenoceptor mRNA levels in the right ventricle of preterm hearts (P = 0.008) but did not alter expression in the left ventricle (P > 0.1). Relative abundance of a 1A -adrenoceptor mRNA was the same in preterm and term piglet hearts (P = > 0.1) but was reduced by maternal glucocorticoid treatment (P < 0.01); a 2A -adrenoceptor mRNA abundance was higher in untreated and glucocorticoid exposed preterm piglet hearts than in term piglets (P < 0.001). There was no difference between male and female piglets in mRNA abundance of any of the genes studied. In conclusion, there is reduced mRNA abundance of ß1-adrenoceptors in the preterm pig heart. If this lower expression of ß-adrenoceptors occurs in human preterm infants, it could explain their poor cardiovascular function and their frequent failure to respond to commonly used inotropes. © 2014 Kim et al.

DOI 10.1371/journal.pone.0092167
Citations Scopus - 8Web of Science - 7
Co-authors E Lumbers
2014 Eiby YA, Lumbers ER, Staunton MP, Wright LL, Colditz PB, Wright IM, Lingwood BE, 'Endogenous angiotensins and catecholamines do not reduce skin blood flow or prevent hypotension in preterm piglets.', Physiological reports, 2 1-13 (2014) [C1]
DOI 10.14814/phy2.12245
Co-authors E Lumbers, Ian Wright
2014 Lumbers ER, Pringle KG, 'Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy', AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 306 R91-R101 (2014) [C1]
DOI 10.1152/ajpregu.00034.2013
Citations Scopus - 14Web of Science - 17
Co-authors E Lumbers, Kirsty Pringle
2014 Sykes SD, Pringle KG, Zhou A, Dekker GA, Roberts CT, Lumbers ER, 'Fetal sex and the circulating renin-angiotensin system during early gestation in women who later develop preeclampsia or gestational hypertension', Journal of Human Hypertension, 28 133-139 (2014) [C1]

There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' ... [more]

There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preeclampsia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy.

DOI 10.1038/jhh.2013.51
Citations Scopus - 11Web of Science - 10
Co-authors E Lumbers, Kirsty Pringle
2014 Rae KM, Weatherall L, Blackwell CC, Pringle K, Smith R, Lumbers E, 'Long conversations: Gomeroi gaaynggal tackles renal disease in the Indigenous community', Australasian Epidemiologist, 21 44-48 (2014) [C2]
Co-authors E Lumbers, Roger Smith, Caroline Blackwell, Kirsty Pringle, Kym Rae
2014 Kandasamy Y, Smith R, Wright IMR, Lumbers ER, 'Reduced nephron endowment in the neonates of Indigenous Australian peoples', JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, 5 31-35 (2014) [C1]
DOI 10.1017/S2040174413000494
Co-authors E Lumbers, Roger Smith, Ian Wright
2013 Zhou A, Dekker GA, Lumbers ER, Lee SY, Thompson SD, McCowan LME, Roberts CT, 'The association of AGTR2 polymorphisms with preeclampsia and uterine artery bilateral notching is modulated by maternal BMI', PLACENTA, 34 75-81 (2013) [C1]
DOI 10.1016/j.placenta.2012.10.007
Citations Scopus - 10Web of Science - 9
Co-authors E Lumbers
2013 Wang Y, Pringle KG, Lumbers ER, 'The effects of cyclic AMP, sex steroids and global hypomethylation on the expression of genes controlling the activity of the renin-angiotensin system in placental cell lines', PLACENTA, 34 275-280 (2013) [C1]
DOI 10.1016/j.placenta.2012.12.018
Citations Scopus - 7Web of Science - 6
Co-authors Kirsty Pringle, E Lumbers
2013 Kandasamy Y, Smith R, Wright IMR, Lumbers ER, 'Extra-uterine renal growth in preterm infants: Oligonephropathy and prematurity', PEDIATRIC NEPHROLOGY, 28 1791-1796 (2013) [C1]
DOI 10.1007/s00467-013-2462-3
Citations Scopus - 18Web of Science - 19
Co-authors Roger Smith, Ian Wright, E Lumbers
2013 Mitchell CM, Sykes SD, Pan X, Pringle KG, Lumbers ER, Hirst JJ, Zakar T, 'Inflammatory and steroid receptor gene methylation in the human amnion and decidua', JOURNAL OF MOLECULAR ENDOCRINOLOGY, 50 267-277 (2013) [C1]
DOI 10.1530/JME-12-0211
Citations Scopus - 3Web of Science - 3
Co-authors E Lumbers, Jon Hirst, Kirsty Pringle
2013 Kandasamy Y, Smith R, Wright IMR, Lumbers ER, 'Relationships between glomerular filtration rate and kidney volume in low-birth-weight neonates', JOURNAL OF NEPHROLOGY, 26 894-898 (2013) [C1]
DOI 10.5301/jn.5000220
Citations Scopus - 4Web of Science - 4
Co-authors Roger Smith, Ian Wright, E Lumbers
2013 Zhou A, Dekker GA, Lumbers ER, Leemaqz SY, Thompson SD, Heinemann G, et al., 'The association of maternal ACE A11860G with small for gestational age babies is modulated by the environment and by fetal sex: a multicentre prospective casecontrol study', MOLECULAR HUMAN REPRODUCTION, 19 618-627 (2013) [C1]
DOI 10.1093/molehr/gat029
Citations Scopus - 4Web of Science - 3
Co-authors E Lumbers
2013 Morrison JL, Lumbers E, Bennet L, Black J, 'Frontiers in Research Review: ISH Early Origins of Hypertension Workshop: Early Life Exposure and Development of a Healthy Heart Introduction: Celebrating Emeritus Scientia Professor Eugenie R Lumbers AM and Professor Caroline McMillen', CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 40 740-742 (2013) [C3]
DOI 10.1111/1440-1681.12180
Co-authors E Lumbers
2013 Lumbers ER, Pringle KG, Wang Y, Gibson KJ, 'The renin-angiotensin system from conception to old age: the good, the bad and the ugly', CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 40 743-752 (2013) [C1]
DOI 10.1111/1440-1681.12098
Citations Scopus - 10Web of Science - 7
Co-authors Kirsty Pringle, E Lumbers
2013 Rae K, Weatherall L, Hollebone K, Apen K, McLean M, Blackwell C, et al., 'Developing research in partnership with Aboriginal communities - strategies for improving recruitment and retention', RURAL AND REMOTE HEALTH, 13 (2013) [C2]
Citations Scopus - 3Web of Science - 4
Co-authors Kym Rae, Caroline Blackwell, E Lumbers, Roger Smith
2013 Eiby YA, Wright LL, Kalanjati VP, Miller SM, Bjorkman ST, Keates HL, et al., 'A Pig Model of the Preterm Neonate: Anthropometric and Physiological Characteristics', PLOS ONE, 8 (2013) [C1]
DOI 10.1371/journal.pone.0068763
Citations Scopus - 22Web of Science - 16
Co-authors E Lumbers
2013 Morrison JL, Lumbers E, Ozanne SE, Suter CM, 'The Australian Early Origins of Hypertension workshop: a celebration of the scientific contributions made by emeritus Scientia professor Eugenie R lumbers AM and professor Caroline McMillen', JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, 4 325-327 (2013) [C3]
DOI 10.1017/S2040174413000391
Citations Scopus - 1Web of Science - 1
Co-authors E Lumbers
2012 Wang Y, Pringle KG, Sykes SD, Marques FZ, Morris BJ, Zakar T, Lumbers ER, 'Fetal sex affects expression of renin-angiotensin system components in term human decidua', Endocrinology, 153 462-468 (2012) [C1]
Citations Scopus - 19Web of Science - 13
Co-authors E Lumbers, Kirsty Pringle
2012 Wang Y, Pringle KG, Chen Y, Zakar T, Lumbers ER, 'Regulation of the renin-angiotensin system (RAS) in BeWo and HTR-8/SVneo trophoblast cell lines', Placenta, 33 634-639 (2012) [C1]
DOI 10.1016/j.placenta.2012.05.001
Citations Scopus - 8Web of Science - 5
Co-authors Kirsty Pringle, E Lumbers
2012 Eiby YA, Lumbers ER, Headrick JP, Lingwood BE, 'Left ventricular output and aortic blood flow in response to changes in preload and afterload in the preterm piglet heart', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 303 (2012) [C1]
DOI 10.1152/ajpregu.00010.2012
Citations Scopus - 11
Co-authors E Lumbers
2011 Pringle KG, Zakar T, Roach DM, Mitchell CM, Hirst JJ, Lumbers ER, 'Molecular evidence of a (pro)renin/(pro)renin receptor system in human intrauterine tissues in pregnancy and its association with PGHS-2', Journal of the Renin-Angiotensin-Aldosterone System, 12 304-310 (2011) [C1]
DOI 10.1177/1470320310376554
Citations Scopus - 16Web of Science - 13
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2011 Marques FZ, Pringle KG, Conquest AL, Hirst JJ, Markus MA, Sarris M, et al., 'Molecular characterization of renin-angiotensin system components in human intrauterine tissues and fetal membranes from vaginal delivery and cesarean section', Placenta, 32 214-221 (2011) [C1]
DOI 10.1016/j.placenta.2010.12.006
Citations Scopus - 26Web of Science - 22
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2011 van der Graaf AM, Zeeman GG, Groen H, Lumbers ER, Roberts C, Dekker GA, 'O15. Non-invasive assessment of hemodynamics in early pregnancy.', Pregnancy hypertension, 1 264 (2011)
Co-authors E Lumbers
2011 Pringle KG, Tadros MA, Callister RJ, Lumbers ER, 'The expression and localization of the human placental prorenin/renin-angiotensin system throughout pregnancy: Roles in trophoblast invasion and angiogenesis?', Placenta, 32 956-962 (2011) [C1]
Citations Scopus - 43Web of Science - 38
Co-authors Robert Callister, Kirsty Pringle, E Lumbers
2011 Brandon AE, Boyce AC, Lumbers ER, Kumarasamy V, Gibson KJ, 'Programming of the renin response to haemorrhage by mild maternal renal impairment in sheep', Clinical and Experimental Pharmacology and Physiology, 38 102-108 (2011) [C1]

The aim of the present study was to test the hypothesis that the renin response to mechanisms activated by haemorrhage is programmed by exposure to maternal renal dysfunction. In ... [more]

The aim of the present study was to test the hypothesis that the renin response to mechanisms activated by haemorrhage is programmed by exposure to maternal renal dysfunction. In 26-27-day-old lambs born to ewes that had reduced renal function (STNxL, n=10) and lambs born to ewes with normal renal function (ConL, n=6), 1.6mL/kg per min of blood was removed over 10min. Under basal conditions, the STNxL group had increased mean arterial pressure (P < 0.05). In response to haemorrhage, mean arterial pressure decreased in the STNxL group (P < 0.001), but there was no significant change in the ConL group. Although plasma renin level increased in both groups (P < 0.05), the peak response was reduced and delayed in the STNxL group. In contrast, the rise in arginine vasopressin (AVP) level was similar in both groups and occurred over the same time course. At 24h, both plasma renin and AVP level were the same as those measured before haemorrhage in both groups. Kidney renin level was similar in the two groups. The attenuated renin response to haemorrhage in the STNxL group might explain the inability to maintain arterial pressure after haemorrhage. The results of the present study suggest that the renin response of the postnatal kidney to reductions in blood volume can be affected by the intrauterine environment. If these changes persist into adulthood, it suggests that permanent programming has occurred. Thus, the ability of an individual to respond to acute severe reductions in blood volume might be determined during intrauterine life. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

DOI 10.1111/j.1440-1681.2010.05473.x
Citations Scopus - 2
Co-authors E Lumbers
2009 Lumbers ER, Kim MY, Burrell JH, Kumarasamy V, Boyce AC, Gibson KJ, et al., 'Effects of intrafetal IGF-I on growth of cardiac myocytes in late-gestation fetal sheep', AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 296 E513-E519 (2009) [C1]
DOI 10.1152/ajpendo.90497.2008
Citations Scopus - 14Web of Science - 11
Co-authors E Lumbers
2009 Brandon AE, Boyce AC, Lumbers ER, Gibson KJ, 'Maternal renal dysfunction in sheep is associated with salt insensitivity in female offspring', Journal of Physiology, 587 261-270 (2009) [C1]

To examine the programming effects of maternal renal dysfunction (created by subtotal nephrectomy in ewes prior to mating; STNx), renal and cardiovascular function were studied in... [more]

To examine the programming effects of maternal renal dysfunction (created by subtotal nephrectomy in ewes prior to mating; STNx), renal and cardiovascular function were studied in 6-month-old male and female offspring of STNx and control pregnancies. After studies were conducted on a low salt diet (LSD) some female offspring underwent salt loading (0.17 m NaCl in the drinking water for 5-7 days; HSD). On LSD both male and female offspring of STNx had similar mean arterial pressures (MAP), heart rates, cardiac outputs and renal function to those measured in offspring of control ewes. In female STNx offspring on a HSD, plasma sodium levels increased and haematocrits fell, indicating volume expansion (P < 0.05). Plasma renin levels were not suppressed despite the increases in plasma sodium concentrations, but aldosterone levels were reduced. In control animals plasma renin levels fell (P < 0.05) but there was no change in plasma aldosterone concentrations. There was a positive relationship between GFR and MAP which was present only in female STNx offspring. In conclusion, in STNx offspring there was an impaired ability to regulate glomerular filtration independent of arterial pressure, renin release was insensitive to a high salt intake and control of aldosterone secretion was abnormal. This study provides evidence of abnormal programming of the renin-angiotensin system and glomerular function in offspring of pregnancies in which there is impaired maternal renal function. © 2009 The Authors. Journal compilation © 2009 The Physiological Society.

DOI 10.1113/jphysiol.2008.158808
Citations Scopus - 5
Co-authors E Lumbers
2008 Brandon AE, Boyce AC, Lumbers ER, Zimanyj MA, Bertram JF, Gibson KJ, 'Glomerular hypertrophy in offspring of subtotally nephrectomized ewes', ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, 291 318-324 (2008) [C1]
DOI 10.1002/ar.20651
Citations Scopus - 7Web of Science - 6
Co-authors E Lumbers
2008 Gibson KJ, Boyce AC, Thomson CL, Chinchen S, Lumbers ER, 'Interactions between subtotal nephrectomy and salt: Effects on blood pressure and renal function in pregnant and nonpregnant ewes', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 294 (2008) [C1]
DOI 10.1152/ajpregu.00842.2006
Citations Scopus - 3
Co-authors E Lumbers
2008 Boyce AC, Gibson KJ, Thomson CL, Lumbers ER, 'Interactions between maternal subtotal nephrectomy and salt: Effects on renal function and the composition of plasma in the late gestation sheep fetus', Experimental Physiology, 93 262-270 (2008) [C1]

Effects of altered maternal salt intake between 122 and 127 days gestation (term is 150 days) were studied in eight fetuses carried by ewes which had renal insufficiency caused by... [more]

Effects of altered maternal salt intake between 122 and 127 days gestation (term is 150 days) were studied in eight fetuses carried by ewes which had renal insufficiency caused by subtotal nephrectomy (STNxF) and seven fetuses carried by intact ewes (IntF). Plasma sodium and osmolality were increased in ewes with subtotal nephrectomy on a high-salt intake (0.17 m NaCl in place of drinking water for 5 days; P < 0.05). The STNxF had normal body weights. A high maternal salt intake did not affect fetal blood pressure or heart rate. Plasma osmolality was higher in STNxF (P < 0.001), and plasma sodium and osmolality were increased by high salt (P < 0.001 and P < 0.04, respectively). The STNxF had higher urinary osmolalities (P = 0.002), which were also increased by a high maternal salt intake (P = 0.03). Renal blood flow fell in STNxF in response to a high maternal salt intake, but increased in IntF (P = 0.003). In STNxF but not IntF, glomerular filtration rate and urinary protein excretion were positively related to fetal plasma renin levels (P = 0.01). It is concluded that the salt intake of pregnant ewes with renal insufficiency affects maternal and fetal osmolar balance, fetal plasma sodium and fetal renal function. Since STNxF also had altered renal haemodynamic responses to high maternal salt and evidence of renin-dependent glomerular filtration and protein excretion, we suggest that interactions between dietary salt and pre-existing maternal renal disease impair glomerular integrity and function in the fetus. © 2007 The Authors.

DOI 10.1113/expphysiol.2007.039149
Citations Scopus - 4
Co-authors E Lumbers
2007 Gibson KJ, Boyce AC, Karime BM, Lumbers ER, 'Maternal renal insufficiency alters plasma composition and renal function in the fetal sheep', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 292 (2007)

To determine the effects of chronic maternal renal insufficiency on fetal renal function, we studied nine fetuses whose mothers underwent subtotal nephrectomy at least 2 mo before... [more]

To determine the effects of chronic maternal renal insufficiency on fetal renal function, we studied nine fetuses whose mothers underwent subtotal nephrectomy at least 2 mo before mating (STNxF) and seven fetuses from intact ewes (IntF) (126-128 days of gestation, term 150 days). STNxF had lower hematocrit (P < 0.05), plasma chloride (P < 0.01), and creatinine levels (P < 0.01), and the length-to-width ratio of their kidneys was reduced (P < 0.05). They excreted twice as much urine (P < 0.05) and sodium (P < 0.01). Total (P < 0.01) and proximal fractional sodium reabsorptions (P < 0.05) were lower in STNxF; distal delivery of sodium (P < 0.05) and distal fractional sodium reabsorption (P < 0.05) were higher. They tended to have suppressed renin levels (P = 0.06). Infusions of amino acids (alanine, glycine, proline, and serine at 0.32 mmol/min for 1 h and 0.64 mmol/min for 2 h intravenously), known to stimulate renal blood flow and glomerular filtration rate in fetal sheep, did so in IntF (P < 0.01). Arterial pressure also increased (P < 0.01). These effects were not observed in STNxF. In summary, chronic maternal renal insufficiency was associated with profound alterations in fetal renal excretion of fluid and electrolytes and impaired renal hemodynamic and glomerular responses to amino acid infusion. Whether these marked changes in the renal function of fetuses carried by STNx ewes are associated with alterations in renal function in postnatal or adult life remains to be determined. Copyright © 2007 the American Physiological Society.

DOI 10.1152/ajpregu.00188.2006
Citations Scopus - 8
Co-authors E Lumbers
2007 Roberts CT, Standen P, Sferruzzi-Perri AN, Owens JA, Kumarasamy V, Lumbers ER, 'Novel but distinct interactions of insulin-like growth factors (IGFs) with the placental renin-angiotensin system in early gestation in guinea pigs', EARLY HUMAN DEVELOPMENT, 83 S146-S146 (2007)
DOI 10.1016/S0378-3782(07)70394-8
Co-authors E Lumbers
2007 Yu ZY, McKay K, van Asperen P, Zheng M, Fleming J, Ginn SL, et al., 'Lentivirus vector-mediated gene transfer to the developing bronchiolar airway epithelium in the fetal lamb', Journal of Gene Medicine, 9 429-439 (2007)

Background: Development of effective and durable gene therapy for treatment of the respiratory manifestations of cystic fibrosis remains a formidable challenge. Obstacles include ... [more]

Background: Development of effective and durable gene therapy for treatment of the respiratory manifestations of cystic fibrosis remains a formidable challenge. Obstacles include difficulty in achieving efficient gene transfer to mature airway epithelium and the need to stably transduce self-renewing epithelial progenitor cells in order to avoid loss of transgene expression through epithelial turnover. Targeting the developing airway epithelium during fetal life offers the prospect of circumventing these challenges. Methods: In the current study we investigated vesicular stomatitis virus glycoprotein (VSVg)-pseudotyped HIV-1-derived lentivirus vector-mediated gene transfer to the airway epithelium of mid-gestation fetal lambs, both in vitro and in vivo. In the in vitro studies epithelial sheet explants and lung organ culture were used to examine transduction of the proximal and more distal airway epithelium, respectively. For the in vivo studies, vector was delivered directly into the proximal airway. Results: We found that even during the early pseudoglandular and canalicular phases of lung development, occurring through mid-gestation, the proximal bronchial airway epithelium was relatively mature and highly resistant to lentivirus-mediated transduction. In contrast, the more distal bronchiolar airway epithelium was relatively permissive for transduction although the absolute levels achieved remained low. Conclusion: This result is promising as the bronchiolar airway epithelium is a major site of pathology in the cystic fibrosis airway, and much higher levels of transduction are likely to be achieved by developing strategies that increase the amount of vector reaching the more distal airway after intratracheal delivery. Copyright ©2007 John Wiley & Sons, Ltd.

DOI 10.1002/jgm.1039
Citations Scopus - 17
Co-authors E Lumbers
2007 Boyce AC, Gibson KJ, Wintour EM, Koukoulas I, Gatford KL, Owens JA, Lumbers ER, 'The kidney is resistant to chronic hypoglycaemia in late-gestation fetal sheep', CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 85 597-605 (2007)
DOI 10.1139/Y07-047
Citations Scopus - 2Web of Science - 2
Co-authors E Lumbers
2006 Matuszek MA, Gibson KJ, Lumbers ER, Simonetta G, 'Impact of cortisol on a-actin content in vascular smooth muscle cells of fetal sheep', Clinical and Experimental Pharmacology and Physiology, 33 197-203 (2006)

1. The effects of gestation on a-actin levels in vascular smooth muscle aortae were studied in 31 fetal sheep, aged 66-144 days (term = 150 days). Aortae were collected post-morte... [more]

1. The effects of gestation on a-actin levels in vascular smooth muscle aortae were studied in 31 fetal sheep, aged 66-144 days (term = 150 days). Aortae were collected post-mortem. 2. Aortae, carotid and femoral arteries from two groups of chronically catheterized fetal sheep (110-114 days) were also examined. One group was infused with cortisol (n = 6; hydrocortisone sodium succinate, total dose 16.8 mg in 48 h) and the control group received saline (0.15 mol/L, 0.33 mL/h, n = 7). 3. Vascular homogenate protein was separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western transfer. a-Actin was identified using a monoclonal mouse anti-a actin antibody and standardized against tissue protein and DNA content. 4. Between 60 and 144 days gestation, there was an exponential increase in the a-actin content of vascular smooth muscle cells from fetal sheep aorta (P < 0.0001). a-Actin concentration (densitometry units (U) relative to DNA 260 nm absorbance (Abs)) was significantly (P < 0.05) higher in the aortae of cortisol-infused (12 601 ± 2499 U/Abs) fetal sheep compared with those that were saline-infused (4514 ± 670 U/Abs). a-Actin (relative to DNA absorbance) of carotid and femoral vessels in cortisol-infused animals (20 659 ± 4812 U/Abs) compared with those that were saline-infused (14 461 ± 2645 U/Abs) was increased, but the difference was not significant. 5. Therefore, the a-actin concentration of the vascular smooth muscle of the aorta increases throughout gestation. Cortisol treatment is associated with further increases in a-actin concentration in the fetal aorta, indicating that the development of large conduit vessels can be altered by this glucocorticoid. © 2006 Blackwell Publishing Asia Pty Ltd.

DOI 10.1111/j.1440-1681.2006.04346.x
Citations Scopus - 2
Co-authors E Lumbers
2006 Gibson KJ, Thomson CL, Boyce AC, Karime BM, Lumbers ER, 'Effects of a reduction in maternal renal mass on pregnancy and cardiovascular and renal function of the pregnant ewe', American Journal of Physiology - Renal Physiology, 290 (2006)

Maternal renal disease is associated with high maternal and fetal morbidity. To establish an animal model to study renal dysfunction in pregnancy and its potential role in program... [more]

Maternal renal disease is associated with high maternal and fetal morbidity. To establish an animal model to study renal dysfunction in pregnancy and its potential role in programming for renal disease and hypertension in adult life, a kidney was removed from each of 16 nonpregnant ewes, and a branch of the renal artery of the remaining kidney was ligated (STNx ewes). The 16 STNx and 15 intact ewes were time mated 2.5-17 mo later and studied at 119-132 days of gestation. STNx ewes demonstrated renal hypertrophy and glomerular hyperfiltration. They had higher diastolic arterial pressures (P < 0.05) and larger left ventricles (P < 0.0005), drank more water (P < 0.01), were hypochloremic (P < 0.01) and hyperglycemic (P < 0.0005), and had higher plasma creatinine levels (P < 0.0005) than intact ewes. Effective renal plasma flows and glomerular filtration rates were lower (P < 0.01) and protein excretion was greater (P < 0.05) in STNx than in intact ewes. Glomerulotubular balance was impaired in STNx ewes. Proximal tubular Na + reabsorption was reduced (P < 0.05), so Na + excretion was increased (P < 0.05). In STNx ewes, filtered K + loads were reduced (P < 0.005), but K + excretion was the same as in intact ewes. There was net K + secretion in STNx ewes; in intact ewes, there was net reabsorption. Plasma renin and angiotensinogen concentrations in STNx and intact ewes were similar, so the hypertension in STNx ewes was not renin dependent. STNx fetuses grew normally, and their blood gases, blood pressure, and heart rates were normal. These alterations in maternal fluid and electrolyte balance and the potential risk of maternal salt depletion or hyperkalemia may adversely affect the fetus. Copyright © 2006 the American Physiological Society.

DOI 10.1152/ajprenal.00241.2005
Citations Scopus - 13
Co-authors E Lumbers
2005 Lumbers ER, Boyce AC, Joulianos G, Kumarasamy V, Barner E, Segar JL, Burrell JH, 'Effects of cortisol on cardiac myocytes and on expression of cardiac genes in fetal sheep', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 288 (2005)

In 17 fetal sheep aged 129 days, the effects of large-dose infusions of cortisol (72.1 mg/day for 2-3 days) on proliferation, binucleation, and hypertrophy of cardiac myocytes, ca... [more]

In 17 fetal sheep aged 129 days, the effects of large-dose infusions of cortisol (72.1 mg/day for 2-3 days) on proliferation, binucleation, and hypertrophy of cardiac myocytes, cardiac expression of angiotensinogen, angiotensin receptor subtypes 1 and 2, Glut-1, glucocorticoid and mineralocorticoid receptors, proteins of the MAPK pathways and calcineurin were studied. Cortisol levels were 8.7 ± 2.3 nM (SE) in 8 control and 1,028 ± 189 nM in 9 treated fetuses (P < 0.001). Cortisol had no effect on myocyte binucleation. Left ventricular free wall (LVFW) uni- and binucleated myocytes were larger in cortisol- treated fetuses (P < 0.001, P < 0.05). Cortisol-treated fetuses had higher right ventricular free wall (RVFW) and LVFW angiotensinogen (Aogen) mRNA levels (treated: 2.30 ± 0.37, n = 8 and 2.05 ± 0.45, n = 7 vs. control: 0.94 ± 0.12, n = 8 and 0.67 ± 0.09, n = 7, P < 0.02). Levels of the glucose transporter Glut-1 mRNA were lower in the LVFW of treated fetuses (0.83 ± 0.23 vs. 1.47 ± 0.30 in control, P < 0.05, n = 7, 8). The higher the cortisol level, the greater the Aogen mRNA level (RVFW, r = 0.61, P < 0.01, n = 16; LVFW, r = 0.83, P < 0.0003, n = 14). There were no other changes in mRNA levels nor in levels of extracellular kinase, JNK, p38, their phosphorylated forms, and calcineurin. Thus high levels of cortisol such as occur after birth do not affect fetal cardiac myocyte binucleation or number but are associated with higher levels of ventricular Aogen mRNA, lower levels of Glut-1 mRNA, and Hypertrophy of LVFW myocytes. These effects could impact on postnatal cardiac development.

DOI 10.1152/ajpregu.00556.2004
Citations Scopus - 50
Co-authors E Lumbers
2005 Boyce AC, Gibson KJ, Wintour EM, Koukoulas I, Lumbers ER, 'Effects of 7-day amino acid infusion on renal growth, function, and renin-angiotensin system in fetal sheep', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 289 (2005)

These experiments examined whether renal growth and the fetal renin-angiotensin system could be stimulated by infusion of amino acids and whether chronic amino acid infusions rest... [more]

These experiments examined whether renal growth and the fetal renin-angiotensin system could be stimulated by infusion of amino acids and whether chronic amino acid infusions restored glomerulotubular balance, which had been disrupted during 4-h infusions. Five fetal sheep aged 122 ± 1 days gestation received an infusion of alanine, glycine, proline and serine in 0.15 M saline at 0.22 mmol/min for 7 days. Six control fetuses were given saline at the same rate (5 ml/h). Kidney wet weights after amino acid infusion were 28% larger than control fetuses (P < 0.05), and renal angiotensinogen mRNA levels were ~2.6-fold higher (P < 0.005). Circulating renin levels and renal renin mRNA levels were suppressed (P < 0.05), and renal renin protein levels tended to be lower. Arterial pressure was increased, and there was a marked, sustained natriuresis and diuresis. Glomerular filtration rate and filtered sodium were ~two-fold higher throughout infusion (P < 0.05). Fractional proximal sodium reabsorption, suppressed at 4 h (from 73.4 ± 6.5 to 53.7 ± 10.2%), did not return to control levels (36.1 ± 3.4% on day 7. P < 0.05). Distal sodium reabsorption was markedly increased (from 79 ± 25 to 261 ± 75 µmol/min by day 7, P < 0.005), but this was not sufficient to restore glomerulotubular balance. The resultant high rates of sodium excretion led to hyponatremia and polyhydramnios. In conclusion, long-term amino acid infusions increased renal angiotensinogen gene expression, kidney weight, and distal nephron sodium reabsorptive capacity but failed to restore. proximal and total glomerulotubular balance. Copyright © 2005 the American Physiological Society.

DOI 10.1152/ajpregu.00055.2005
Citations Scopus - 7
Co-authors E Lumbers
2003 Burrell JH, Boyn AM, Kumarasamy V, Hsieh A, Head SI, Lumbers ER, 'Growth and Maturation of Cardiac Myocytes in Fetal Sheep in the Second Half of Gestation', Anatomical Record - Part A Discoveries in Molecular, Cellular, and Evolutionary Biology, 274 952-961 (2003)

Right (RVFW) and left (LVFW) ventricular free wall cardiac myocytes were collected from 25 fetal sheep aged 77-146 days gestation (term = 150 days gestation), six saline-infused c... [more]

Right (RVFW) and left (LVFW) ventricular free wall cardiac myocytes were collected from 25 fetal sheep aged 77-146 days gestation (term = 150 days gestation), six saline-infused catheterized fetal sheep (129 GD), and five lambs to measure gestational changes in uni- and binucleated cardiac myocyte numbers and cell volumes by confocal microscopy. At 77 days gestation, 2% of the myocytes were binucleated, which increased to 50% at 135 days gestation and 90% at 4-6 weeks after birth. RVFW uni- and binucleated myocytes were larger than those in the LVFW, and cell volumes of RVFW uni- and binucleated and LVFW binucleated myocytes (but not LVFW uninucleated myocytes) increased with gestation. Before birth, the approximate number of myocytes was greater in the LVFW than in the RVFW (P < 0.001). Before 110 GD, cardiac growth appeared to be due to myocyte hyperplasia, as approximate myocyte numbers and VFW weight increased at the same rate. After 110 days gestation, the approximate myocyte number/g VFW weight decreased, which suggests that myocyte hypertrophy, as well as hyperplasia, was occurring in association with the appearance of a greater proportion of binucleated cells after that time. By 4-6 weeks of age, there was marked hypertrophy of myocytes and an apparent reduction in myocyte number. © 2003 Wiley-Liss, Inc.

Citations Scopus - 74
Co-authors E Lumbers
2003 O'Connell AEO, Boyce AC, Lumbers ER, Gibson KJ, 'The effects of asphyxia on renal function in fetal sheep at midgestation', Journal of Physiology, 552 933-943 (2003)

To determine whether damage to the fetal kidneys plays a role in the formation of hydrops fetalis following a severe asphyxial episode, six chronically catheterised fetal sheep, a... [more]

To determine whether damage to the fetal kidneys plays a role in the formation of hydrops fetalis following a severe asphyxial episode, six chronically catheterised fetal sheep, at 0.6 gestation (90 days; term 150 days), were subjected to 30 min of complete umbilical cord occlusion. During the occlusion period, mean arterial pressure, heart rate and renal blood flow decreased (P < 0.001). There were falls in arterial pH and P O2 and a rise in P CO2 (P < 0.001). Urine flow rate decreased (P < 0.005), as did the excretion rates of sodium and osmoles (P < 0.05). However, by 60 min after release of occlusion, urine flow rate was similar to control values. By the end of day 1, most renal variables returned to normal. At post-mortem, 72 h after occlusion, all asphyxiated fetuses showed gross signs of hydrops. Body weight was higher (P < 0.05) due to fluid accumulation in the peritoneal (P < 0.001) and pleural cavities (P < 0.05) as well as subcutaneously (P < 0.05). Amniotic/allantoic fluid volume was increased (P < 0.05). Kidney histology was normal except for clusters of apoptotic cells in some proximal tubules. In conclusion, this severe asphyxial episode caused surprisingly little damage to the kidney and the changes in renal function were very transient. Thus renal damage was not important in the development of hydrops. Possibly, the midgestation fetal kidney has a limited capacity to increase urinary salt and water excretion in response to increased fluid delivery across the placenta.

DOI 10.1113/jphysiol.2003.050062
Citations Scopus - 12
Co-authors E Lumbers
2003 Lumbers ER, Yu ZY, Crawford EN, 'Effects of fetal behavioral states on renal sympathetic nerve activity and arterial pressure of unanesthetized fetal sheep', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 285 (2003)

Fetal behavior, renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were studied 1-3 days after surgery in seven fetal sheep (aged 127-136 d... [more]

Fetal behavior, renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were studied 1-3 days after surgery in seven fetal sheep (aged 127-136 days). Five behavioral states were defined from chart recordings of electrocortical (electrocorticographic; ECoG) activity and eye, limb, and breathing movements. Most records were of high-voltage ECoG (HV) or low-voltage (LV) ECoG with breathing (LV B ); 6.7 ± 1.7% were LV ECoG with no breathing (LV 0 ). RSNA was lower in LV 0 (P < 0.001) and greater in LV B than in HV (P < 0.05). MAP was lower in both LV states than in HV and when the fetuses went from LV to HV (P < 0.001 to P < 0.03). HR was highest in HV (P < 0.001). In HV and LV B and when the fetus went from LV to HV, MAP and HR were inversely related (P = 0.012-0.003). In LV B and from LV to HV there were direct relationships between MAP and RSNA (P = 0.0014, P = 0.08), and when the fetus went from LV to HV there was also an inverse relationship between HR and RSNA (P = 0.02). Thus fetal RSNA, MAP, and HR are affected by behavioral state as is fetal cardiovascular control. The increase in RSNA during fetal breathing showed that there was an altered level of fetal RSNA associated with fetal breathing activity.

Citations Scopus - 4
Co-authors E Lumbers
2003 Lumbers ER, Yu ZY, Crawford EN, 'Effects of fetal behavioral states on renal sympathetic nerve activity and arterial pressure of unanesthetized fetal sheep.', American journal of physiology. Regulatory, integrative and comparative physiology, 285 R908-R916 (2003)
Co-authors E Lumbers
2002 Marsh AC, Lumbers ER, Gibson KJ, 'Renal, cardiovascular and endocrine responses of fetal sheep at 0.8 of gestation to an infusion of amino acids', Journal of Physiology, 540 717-728 (2002)

Amino acid infusions increase renal blood flow (RBF) and glomerular filtration rate (GFR) and stimulate tubular reabsorption in adults. To characterize the effects of amino acids ... [more]

Amino acid infusions increase renal blood flow (RBF) and glomerular filtration rate (GFR) and stimulate tubular reabsorption in adults. To characterize the effects of amino acids on fetal renal haemodynamics, tubular sodium reabsorption, acid-base homeostasis and plasma renin levels, 11 chronically catheterized fetal sheep aged 121 ± 1 days (term ~150 days) were infused i.v. for 4 h with alanine, glycine, proline and serine (0.1, 0.1, 0.06 and 0.06 mmol min -1 , respectively) in 0.15 M saline at 0.165 ml min -1 . Eight control fetuses were given saline. During amino acid infusion, plasma amino acid levels increased up to 20-fold (P < 0.005). GFR increased by 50 ± 8% (P < 0.00 1); there was only a small transient increase in RBF. Proximal fractional sodium reabsorption fell from 74.6 ± 2.9 to 55.5 ± 5.4% (P < 0.005). Distal sodium delivery increased, but a smaller percentage of this distal sodium load was reabsorbed (P < 0.005). Thus fractional sodium reabsorption fell from 95.5 ± 0.9 to 81.4 ± 2.0% (P < 0.005). There was a large diuresis, natriuresis, kaliuresis and increase in osmolar excretion (P < 0.005). Plasma sodium and chloride concentrations fell (P < 0.005). Plasma osmolality did not change. Plasma renin levels fell (P < 0.05), cortisol levels increased (P < 0.05), and there was a compensated metabolic acidosis. Thus the fetal sheep kidney demonstrated a remarkable functional capacity to respond to amino acid infusion. The increase in filtration fraction and the lack of an increase in RBF suggest that efferent arteriolar vasoconstriction occurred, a very different response from the renal vasodilatation seen in adult animals.

DOI 10.1113/jphysiol.2001.013448
Citations Scopus - 8
Co-authors E Lumbers
2002 Marsh AC, Lumbers ER, Gibson KJ, 'Renal, cardiovascular and endocrine responses of fetal sheep at 0.8 of gestation to an infusion of amino acids.', The Journal of physiology, 540 717-728 (2002)
Co-authors E Lumbers
2002 McMullen JR, Gibson KJ, Lumbers ER, Burrell JH, '125I[Sar1Ile8] Angiotensin II has a different affinity for AT1 and AT2 receptor subtypes in ovine tissues', Regulatory Peptides, 105 83-92 (2002)

Iodinated angiotensin II (Ang II) and its analogues are often assumed to have equal affinities for AT 1 and AT 2 receptor subtypes. However, using saturation and competition bin... [more]

Iodinated angiotensin II (Ang II) and its analogues are often assumed to have equal affinities for AT 1 and AT 2 receptor subtypes. However, using saturation and competition binding assays in several tissues from pregnant, nonpregnant, and fetal sheep, we found the affinity of 125 I[Sar 1 Ile 8 ] Ang II for Ang II receptors was different (P < 0.05) between tissue types. The dissociation constants (Kd) and half maximal displacements of [Sar 1 Ile 8 ] Ang II (Sar IC 50 ) were directly related (P < 0.05) to proportions of AT 1 receptors, and inversely related (P < 0.05) to proportions of AT 2 receptors in tissues from all groups combined, in tissues from individual groups (pregnant, nonpregnant or fetal), and in some individual tissues (uterine arteries and aortae). This suggests that 125 I[Sar 1 Ile 8 ] Ang II has a different affinity for AT 1 and AT 2 receptors in ovine tissues. The Kds of 125 I[Sar 1 Ile 8 ] Ang II for "pure" populations of AT 1 and AT 2 receptors were 1.2 and 0.3 nM, respectively, i.e. affinity was four-fold higher for AT 2 receptors. We corrected the measured proportions of the receptor subtypes using their fractional occupancies. In tissues which contained at least 10% of each receptor subtype, the corrected proportions were significantly altered (P < 0.05), even in some tissues, to the extent of being reversed. © 2002 Elsevier Science B.V. All rights reserved.

Citations Scopus - 3
Co-authors E Lumbers
2002 McMullen JR, Gibson KJ, Lumbers ER, Burrell JH, '125I[Sar(1)Ile(8)] angiotensin II has a different affinity for AT(1) and AT(2) receptor subtypes in ovine tissues.', Regulatory peptides, 105 83-92 (2002)
Co-authors E Lumbers
2002 Yu ZY, Lumbers ER, 'Effects of birth on baroreceptor-mediated changes in heart rate variability in lambs and fetal sheep', Clinical and Experimental Pharmacology and Physiology, 29 455-463 (2002)

1. In adult unanaesthetized sheep, there is a V-shaped relationship between mean arterial pressure (MAP) and heart rate variability (HRV), measured in both time and frequency doma... [more]

1. In adult unanaesthetized sheep, there is a V-shaped relationship between mean arterial pressure (MAP) and heart rate variability (HRV), measured in both time and frequency domains. In contrast, in fetal sheep, there is only a positive direct relationship between MAP and HRV, which is determined by the cardiac vagus. We postulated that by the time lambs were 8-10 days old, the 'adult like' V-shaped relationship between MAP and HRV would be present and it may appear at or after birth. To test these hypotheses, experiments were performed in six chronically catheterized fetal sheep (aged 132-138 days gestation), 10 newborn sheep (within 10 h of birth) and 10 lambs (aged 8-10 days). The relationships between MAP and HRV (in both time and frequency domains) were studied before and during ß-adrenoreceptor blockade with propranolol and before and during cardiac vagal blockade with atropine. 2. In 8-10-day-old lambs, V-shaped relationships between MAP and HRV (measured in both time and frequency domain) were obtained. The negative limb of this V-shaped relationship between MAP and HRV was present after cardiac vagal blockade. The positive slope of the V was present after ß-adrenoreceptor blockade. 3. In 4-h-old newborn sheep, there was no relationship between MAP and HRV (measured in the time domain), but between 7 and 10 h of age a negative relationship was found during treatment with atropine and a positive relationship was found during ß-adrenoreceptor blockade, when HRV was measured in both time and frequency domains. 4. As described previously, there was only a positive relationship between MAP and HRV in fetal sheep, which was abolished by atropine but not affected by ß-adrenoreceptor blockade. 5. Thus, until relatively late in fetal life, baroreceptor-modulated changes in efferent cardiac sympathetic tone, determined by measuring the effects of autonomic blockade on HRV, could not be elicited, although reflex vagal pathways were active. By 7-10 h after birth, baroreceptor-modulated changes in efferent cardiac sympathetic tone were present. It was possible using measurements of HRV made in the time domain to show that these baroreceptor-modulated cardiac sympathetic effects became stronger over the first 10 days of life (P < 0.01). These studies are the first to show that the influence of baroreceptor-mediated changes in cardiac sympathetic tone on HRV increases in early life. This is probably because maturation of sympathetic innervation of the fetal sheep heart is occurring at this age.

DOI 10.1046/j.1440-1681.2002.03678.x
Citations Scopus - 13
Co-authors E Lumbers
2002 Yu ZY, Lumbers ER, Simonetta G, 'The cardiovascular and renal effects of acute and chronic inhibition of nitric oxide production in fetal sheep', Experimental Physiology, 87 343-351 (2002)

The acute and long-term effects of blockade of nitric oxide (NO) production were studied in six chronically catheterised fetal sheep aged from 116 and 118 days; six untreated feta... [more]

The acute and long-term effects of blockade of nitric oxide (NO) production were studied in six chronically catheterised fetal sheep aged from 116 and 118 days; six untreated fetal sheep received injections of saline. Injection of 10 mg (kg maternal body wt) -1 of the nitric oxide synthase (NOS) inhibitor N ¿ -nitro-L-arginine (NOLA) to the fetus, caused an immediate rise in fetal mean arterial pressure (MAP, P < 0.005) and a reflex fall in fetal heart rate (FHR, P < 0.001). Plasma renin concentration (PRC) fell from 8.4 ± 3.3 to 1.5 ± 0.3 ng ml -1 h -1 (P < 0.001) and was dependent on MAP (P = 0.001). Glomerular filtration rate (GFR) tended to increase, but renal blood flow (RBF) velocity decreased (P < 0.001). Thus filtration fraction (FF) increased (P < 0.025). Urine flow and sodium excretion increased (P < 0.001 for both). Fractional sodium reabsorption decreased (P < 0.05). In fetuses treated with NOLA, arterial pressure was found to affect glomerular haemodynamics and renal tubular handling of sodium. No such relationships were observed in untreated fetuses. The vascular responses to acetylcholine tended to be less (P = 0.07) and the responses to noradrenaline were enhanced in NOLA-treated fetuses. There were no changes in untreated fetuses. Fetuses were then injected twice daily with either 5 mg kg -1 NOLA or saline for the next 2 days. On the 4th day, injection of 10 mg kg -1 NOLA did not have any effects on MAP, FHR or renal function. However, the pressor responses to angiotensin II (Ang II) were enhanced (P < 0.005), as was the response to noradrenaline but to a lesser extent. It is concluded that endothelial production of NO maintains normal fetal blood pressure, renal vascular resistance and fetal renal function. When NO production was blocked by repeated injections of NOLA, other vasodilator pathways took over the maintenance of cardiovascular and renal vascular tone. However, alterations in both cardiovascular and renal function were still present. That is, there was increased pressor sensitivity to exogenous Ang II and unmasking of effects of arterial pressure on glomerular and tubular function.

DOI 10.1113/eph8702339
Citations Scopus - 3
Co-authors E Lumbers
2002 Lumbers ER, 'Exercise in pregnancy: Physiological basis of exercise prescription for the pregnant woman', Journal of Science and Medicine in Sport, 5 20-31 (2002)

A pregnant woman participated in cycling events in the 2000 Olympics. Recently there was concern about the participation of a pregnant woman in the Australian netball team. More a... [more]

A pregnant woman participated in cycling events in the 2000 Olympics. Recently there was concern about the participation of a pregnant woman in the Australian netball team. More and more women are anxious to pursue sports during their pregnancies and to maintain condition. For the clinician or sports physician caring for women who want to maintain a high-level of physical activity there is no simple exercise prescription. It is probable that continuing exercise by women who are already conditioned will not result in foetal compromise, unless there are hidden or unknown complications of pregnancy. Pregnant women should probably exercise within limits that do not cause severe discomfort and should, as pregnancy progresses, be prepared to moderate the intensity and duration of their exercise programs to avoid risks and injury. It is probably not advisable for women to begin high intensity exercise programs when pregnant, although moderate exercise is beneficial to both mother and baby. The type of activity that is undertaken has to be taken into consideration and in particular the adverse effects of supine activity in late gestation recognised.

Citations Scopus - 12
Co-authors E Lumbers
2001 Marsh AC, Gibson KJ, Wu J, Owens PC, Owens JA, Lumbers ER, 'Insulin-like growth factor I alters renal function and stimulates renin secretion in late gestation fetal sheep', JOURNAL OF PHYSIOLOGY-LONDON, 530 253-262 (2001)
DOI 10.1111/j.1469-7793.2001.0253l.x
Citations Web of Science - 11
Co-authors E Lumbers
2001 Marsh AC, Gibson KJ, Wu J, Owens PC, Owens JA, Lumbers ER, 'Insulin-like growth factor I alters renal function and stimulates renin secretion in late gestation fetal sheep', Journal of Physiology, 530 253-262 (2001)

1. While it is known that treatment with insulin-like growth factor I (IGF-I) stimulates growth of the fetal kidney, nothing is known about the short term or long term effects of ... [more]

1. While it is known that treatment with insulin-like growth factor I (IGF-I) stimulates growth of the fetal kidney, nothing is known about the short term or long term effects of IGF-I on fetal renal function. To investigate the acute effects of IGF-I on fetal renal function and on the activity of the fetal renin-angiotensin system, studies were carried out in 12 chronically catheterized fetal sheep aged 120 ± 1 days, before and during a 4 h I.V. infusion of IGF-I at 80 µg h -1 . Seven control fetuses were infused over the same period with vehicle (0.1% bovine serum albumin in 0.15 M saline). 2. IGF-I infusion increased plasma IGF-I concentrations by about 80%. There was a small fall in arterial P O2 (P < 0.01), arterial P CO2 increased (P < 0.05), plasma lactate levels increased (P < 0.01) and arterial pH fell (P < 0.05). Fractional bicarbonate reabsorption increased and bicarbonate excretion decreased (P < 0.05). 3. Infusions of IGF-I had no sustained effect on fetal arterial pressure. Glomerular filtration rate (GFR) did not change significantly during IGF-I infusion, but renal blood flow (RBF) fell (P < 0.05). Therefore filtration fraction relative to control values increased (P < 0.05), suggesting that efferent arteriolar vasoconstriction had occurred. 4. IGF-I infusion led to an antidiuresis (P < 0.01), a rise in urinary osmolality (P < 0.05) and a fall in free water clearance (P < 0.01). Since fetal P O2 fell, it is probable that these effects were mediated by arginine vasopressin. 5. The excretion rates of sodium, chloride and phosphate were all reduced by 4 h of infusion (P < 0.05), because their fractional reabsorption rates were all increased (sodium, P < 0.01; chloride, P < 0.01; and phosphate, P < 0.05). 6. Plasma renin concentration increased by 275 ± 52% during infusion of IGF-I (P < 0.005). Plasma renin activity also increased (P < 0.005), while circulating angiotensinogen concentrations fell (P < 0.05). 7. In the adult, IGF-I increases both RBF and GFR, enhances tubular reabsorption and stimulates the renin-angiotensin system. In the fetus, however, it decreased RBF and had no effect on GFR, but was associated with enhanced tubular function and intense stimulation of renin secretion. Some of these effects of IGF-I on fetal renal function may be involved in maturation of the kidney in preparation for life after birth.

DOI 10.1111/j.1469-7793.2001.0253l.x
Citations Scopus - 12
Co-authors E Lumbers
2001 McMullen JR, Gibson KJ, Lumbers ER, Burrell JH, 'Selective down-regulation of AT2 receptors in uterine arteries from pregnant ewes given 24-h intravenous infusions of angiotensin II', Regulatory Peptides, 99 119-129 (2001)

Previously, we showed that uterine arteries from late gestation pregnant ewes infused intravenously with angiotensin II (Ang II) for 24 h, displayed heightened responsiveness to A... [more]

Previously, we showed that uterine arteries from late gestation pregnant ewes infused intravenously with angiotensin II (Ang II) for 24 h, displayed heightened responsiveness to Ang II in vitro. Furthermore, we found that a small population of ewes with a "preeclampsia-like" disorder also displayed this. Therefore, we have investigated the density and affinity of Ang II receptor subtypes in the uterine arteries from these groups. Ang II receptor binding was measured using 125 I [Sar 1 Ile 8 ] Ang II. Proportions of AT 1 and AT 2 receptors were determined by inhibiting 125 I [Sar 1 Ile 8 ] Ang II with losartan (AT 1 antagonist) or PD 123319 (AT 2 antagonist). Uterine arteries from 24-h Ang II-infused ewes had a lower proportion of AT 2 receptor (56.2 ± 2.3%) than control (saline-infused) ewes (84.1 ± 1.0%; P < 0.05). The density of AT 2 receptors was reduced (P < 0.05) while the density of AT 1 receptors was not different. Thus, 24-h infusions of Ang II selectively down-regulated AT 2 receptors in the uterine artery, resulting in heightened Ang II reactivity. By contrast, the binding properties of Ang II receptor subtypes in uterine arteries from ewes with the "preeclampsia-like" disorder were not different from control ewes. © 2001 Elsevier Science B.V.

DOI 10.1016/S0167-0115(01)00242-7
Citations Scopus - 16
Co-authors E Lumbers
2001 Lumbers ER, Yu ZY, Gibson KJ, 'The selfish brain and the barker hypothesis', Clinical and Experimental Pharmacology and Physiology, 28 942-947 (2001)

1. Brain sparing is a feature of intra-uterine growth retardation (IUGR). This implies that there is a redistribution of metabolic supply so that body growth slows to a greater ex... [more]

1. Brain sparing is a feature of intra-uterine growth retardation (IUGR). This implies that there is a redistribution of metabolic supply so that body growth slows to a greater extent than brain growth. 2. Intra-uterine growth retardation, as evidenced by a low birthweight for gestational age is a predisposing factor for hypertension, cardiovascular disease and diabetes mellitus in adult life. 3. In species like humans, nephrogenesis is complete before birth. In the rat, it is completed shortly after birth. In both species, it can be shown that either undernutrition or IUGR is associated with reduced nephron number. 4. It has been proposed that oligonephropathy results in hyperfiltration, which ultimately leads to glomerulosclerosis and hypertension. The renin-angiotensin system (RAS) is necessary for normal renal development and fetal renal function. In the rat, blockade of the RAS in the first weeks of life by pharmacological agents reduces glomerular number and has been shown to cause hypertension in adult life. Renal denervation reduces the activity of the fetal RAS and also causes abnormal development of the renin-secreting cells. 5. There is tonic renal sympathetic nerve activity in the late gestation fetal sheep. The level of renal sympathetic nerve activity (RSNA) is influenced by the fetal behavioural state. 6. However, interactions between the developing kidney and the developing sympathetic nervous system are poorly understood. On the one hand, renal innervation may be important in the provision of neurotrophic factors that stimulate the development of the RAS and kidney. On the other, high levels of RSNA associated with circulating catecholamines and vasopressin may cause vasoconstriction and limit nephrogenesis. This latter effect could be a predisposing factor to adult hypertension and cardiovascular disease.

DOI 10.1046/j.1440-1681.2001.03554.x
Citations Scopus - 42
Co-authors E Lumbers
2001 Marsh AC, Gibson KJ, Wu J, Owens PC, Owens JA, Lumbers ER, 'Chronic effect of insulin-like growth factor I on renin synthesis, secretion, and renal function in fetal sheep', AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 281 R318-R326 (2001)
Citations Web of Science - 19
Co-authors E Lumbers
2001 Marsh AC, Gibson KJ, Wu J, Owens PC, Owens JA, Lumbers ER, 'Chronic effect of insulin-like growth factor I on renin synthesis, secretion, and renal function in fetal sheep', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 281 (2001)

In the adult, insulin-like growth factor I (IGF-I) increases glomerular filtration rate (GFR) and renal blood flow (RBF) during both acute and chronic treatment. To study its effe... [more]

In the adult, insulin-like growth factor I (IGF-I) increases glomerular filtration rate (GFR) and renal blood flow (RBF) during both acute and chronic treatment. To study its effects on the developing kidney, chronically catheterized fetal sheep (120 ± 1 days gestation) were infused intravenously for up to 10 days with 80 µg/h IGF-I (n = 5) or vehicle (0.1% BSA in saline, n = 6). In contrast to previous acute studies in adult rats and humans, after 4 h of IGF-I fetal GFR and RBF were unchanged. Fractional sodium reabsorption increased (P < 0.05). However, by 4 days, GFR per kilogram had risen by 35 ± 13% (P < 0.05), whereas RBF remained unchanged. Tubular growth and maturation may have occurred, as proximal tubular sodium reabsorption increased by ~35% (P < 0.005). Therefore, despite a marked increase in filtered sodium (~30%, P < 0.05), fractional sodium reabsorption did not change. Although the effects of IGF-I on renal function were delayed, plasma renin activity and concentration were both elevated after 4 h and remained high at 4 days (P < 0.05). Despite this, arterial pressure and heart rate did not change. Kidneys of IGF-Iinfused fetuses weighed ~30% more (P = 0.05) and contained ~75% more renin than control fetuses (P < 0.005). Thus, in the fetus, the renal effects of long-term IGF-I infusion are very different from the adult, possibly because IGF-I stimulated kidney growth.

Citations Scopus - 22
Co-authors E Lumbers
2001 Lumbers ER, Gunn AJ, Zhang DY, Wu JJ, Maxwell L, Bennet L, 'Nonimmune hydrops fetalis and activation of the renin-angiotensin system after asphyxia in preterm fetal sheep', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 280 (2001)

This study examined the hypothesis that the development of hydrops fetalis after asphyxia in the 0.6 gestation sheep fetus would be associated with activation of the fetal renin-a... [more]

This study examined the hypothesis that the development of hydrops fetalis after asphyxia in the 0.6 gestation sheep fetus would be associated with activation of the fetal renin-angiotensin system (RAS). Fetuses were randomly assigned to either sham occlusion (n = 7) or to 30 min of asphyxia induced by complete umbilical cord occlusion for 30 rain (n = 8). Asphyxia led to severe bradycardia and hypotension that resolved after release of occlusion. After occlusion, plasma renin concentration was significantly increased in the asphyxia group compared with controls (P < 0.005) after 3 min (16.3 ±5.3 vs. 4.1 ±1.3 ng·ml -1 ·h -1 ), and 72 h (30.6 ±6.3 vs. 3.7 ±1.2 ng·ml -1 ·h -1 ). Renal renin concentrations and mRNA levels were significantly greater in the asphyxia group after 72 h of recovery. All fetuses in the asphyxia group showed generalized tissue edema, ascites, and pleural effusions after 72 h of recovery. In conclusion, asphyxia in the preterm fetus caused sustained activation of the RAS, which was associated with hydrops fetalis.

Citations Scopus - 17
Co-authors E Lumbers
2001 Lumbers ER, Gunn AJ, Zhang DY, Wu JJ, Maxwell L, Bennet L, 'Nonimmune hydrops fetalis and activation of the renin-angiotensin system after asphyxia in preterm fetal sheep.', American journal of physiology. Regulatory, integrative and comparative physiology, 280 R1045-R1051 (2001)
Co-authors E Lumbers
2001 Burrell JH, Hegarty BD, McMullen JR, Lumbers ER, 'Effects of gestation on ovine fetal and maternal angiotensin receptor subtypes in the heart and major blood vessels', Experimental Physiology, 86 71-82 (2001)

Previous studies in fetal sheep have concluded that (a) the vascular AT 1 angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other s... [more]

Previous studies in fetal sheep have concluded that (a) the vascular AT 1 angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other systemic blood vessels, and (b) carotid arterial rings contract in vitro in response to Ang II. These contractions are blocked by the AT 1 specific receptor antagonist losartan. The aim of the present study was to resolve the apparent contradiction of these earlier conclusions, by examining the distribution of Ang II receptor subtypes in different regions of the ovine fetal cardiovascular system, and to find out at what stage in development AT 1 receptors first appear. We measured AT 1 and AT 2 receptors in hearts, carotid arteries, aortae and umbilical vessels from fetal sheep aged 65-144 days (term ¿150 days), and in hearts and aortae from lambs, and adult pregnant and non-pregnant ewes. Both AT 1 and AT 2 receptors were present in aortae of fetuses > 118 days gestation, and carotid arteries of fetuses > 121 days gestation, while in younger fetuses only AT 2 receptors were found. The proportion of carotid artery and aortic AT 1 receptors increased with age, while the proportion of AT 2 receptors decreased. The internal umbilical artery contained both subtypes, but there was no relationship between receptor density and gestational age. The external umbilical artery had only AT 1 receptors. The highest density of Ang II receptors was found in the fetal heart where the AT 2 subtype predominated. The density of fetal cardiac Ang II receptors declined with age (r = -0.44, P < 0.02) due to the decrease in the AT 2 subtype. The density in late gestation fetal hearts was greater than in lamb or adult hearts (P < 0.001). Our study shows that fetal systemic blood vessels contain AT 1 receptors, and we have documented for the first time that the appearance of AT 1 receptors is both different in different regions of the fetal cardiovascular system and is developmentally regulated. Together with the in vitro contractile studies, this suggests that Ang II can play an important role in fetal blood pressure regulation via AT 1 receptors in the fetal systemic vasculature, as well in the umbilicoplacental vessels.

DOI 10.1113/eph8602075
Citations Scopus - 37
Co-authors E Lumbers
2000 Hegarty BD, Burrell JH, Gibson KJ, McMullen JR, Lumbers ER, 'Effect of cortisol on fetal ovine vascular angiotensin II receptors and contractility', European Journal of Pharmacology, 406 439-448 (2000)

The renin angiotensin system is important in the regulation of fetal blood pressure. This study investigated the expression of angiotensin AT 1 and AT 2 receptors in the ovine f... [more]

The renin angiotensin system is important in the regulation of fetal blood pressure. This study investigated the expression of angiotensin AT 1 and AT 2 receptors in the ovine fetal heart, aorta and umbilical artery, and how these receptors are affected by cortisol. Cortisol infusion into the fetus has previously been shown to cause an increase in fetal blood pressure. We hypothesised that this effect of cortisol is mediated by upregulation of the angiotensin AT 1 receptor. Binding studies performed on tissues with intact endothelium demonstrated both receptor subtypes in the fetal aorta and right ventricle, although the latter contained mainly angiotensin AT 2 receptors. In contrast, only angiotensin AT 1 receptors were found in the umbilical artery. Cortisol infusion into fetuses (3 mg/day for 3-5 days) caused a physiological increase in plasma cortisol levels to 29 ± 4 nM. This was associated with an increase in systolic pressure (57.8 ± 1.7 vs. 52.2 ± 1.5 mm Hg, P < 0.05), but cortisol had no effect on the density or affinity of angiotensin receptors, nor on the in vitro contractile responses of carotid and umbilical arterial rings to 5-µM angiotensin II. In conclusion, this study has demonstrated differential expression of angiotensin AT 1 and AT 2 receptors in the different regions of the ovine fetal cardiovascular system and that the angiotensin AT 1 receptor is functional. The lack of any effect of low doses of cortisol on these receptors and on the contractility of isolated fetal vessels to angiotensin II suggests cortisol acts by other mechanisms to raise fetal arterial pressure. (C) 2000 Elsevier Science B.V.

DOI 10.1016/S0014-2999(00)00698-1
Citations Scopus - 13
Co-authors E Lumbers
2000 Yu ZY, Lumbers ER, 'Measurement of baroreceptor-mediated effects on heart rate variability in fetal sheep', Pediatric Research, 47 233-239 (2000)

To determine if alterations in arterial pressure influenced fetal heart rate variability (HRV), experiments were carried out in chronically catheterized fetal sheep aged 128-138 d... [more]

To determine if alterations in arterial pressure influenced fetal heart rate variability (HRV), experiments were carried out in chronically catheterized fetal sheep aged 128-138 d. Arterial pressure was raised or lowered by intravenous infusion of phenylephrine or sodium nitroprusside, and the effects on heart rate (HR) and HRV were measured (HRV, as the coefficient of variation (CV) in mean pulse interval or by power spectral analysis). Experiments were carried out before and during ß-adrenoceptor blockade with propranolol or before and during cardiac vagal blockade with atropine. There were positive relationships between mean arterial pressure and HRV (slope = 0.074 ± 0.001, r = 0.81 ± 0.06, p < 0.001, measured as the CV of pulse interval) and between mean arterial pressure and power spectral density (slope = 4 ± 0.5, r = 0.89 ± 0.02, p < 0.001) in the frequency range 0.04- 0.08 Hz. ß-adrenoceptor blockade had no effect on these relationships, but they were abolished by cardiac vagal blockade. The sigmoid relationship between fetal HR and mean arterial pressure, i.e. the cardiac baroreflex, was affected, however, by blockade of cardiac sympathetics and abolished by blockade of cardiac vagal activity. Thus, fetal HRV was affected by alterations in arterial pressure, and these effects depended on the integrity of the cardiac vagus, not on alterations in cardiac sympathetic activity. Therefore, although baroreflex control of fetal HR depends on the integrity of both sympathetic and parasympathetic efferent pathways, baroreceptor- induced changes in HRV depend only on the cardiac vagus.

Citations Scopus - 24
Co-authors E Lumbers
2000 Yu ZY, Lumbers ER, 'Effect of cold on fetal heart rate and its variability', Clinical and Experimental Pharmacology and Physiology, 27 607-611 (2000)

1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interv... [more]

1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interval (PI) and by power spectral analysis (PSA), were measured in 10 chronically catheterized fetal sheep aged 140-144 days. To determine the extent to which effects on HR and HRV were mediated by the sympathoadrenal neuroendocrine axis and the cardiac vagus, experiments were performed before and after ß-adrenoreceptor blockade with propranolol (n = 12 fetuses) or before and after cardiac vagal blockade with atropine (n = 4 fetuses). 2. Injection of ice-cold saline over the skin caused an immediate rise in mean arterial pressure (MAP) from 46 ± 1 to 55 ± 1 mmHg (P < 0.001) and HR from 156 ± 2 to 182 ± 2 b.p.m. (P < 0.001). Heart rate variability, measured as CV of PI, rose from 3.5 ± 0.2 to 8.0 ± 0.2% (P < 0.001) and total power spectral density (PSD) increased from 78 ± 6 to 278 ± 16 units (P < 0.001) as measured by PSA. Within 100s, MAP, HR and HRV had returned to baseline. 3. ß-Adrenoreceptor blockade abolished all these changes in HR, HRV and PSD, but had no effect on changes in MAP. Atropine had no demonstrable effect on the responses to cold. 4. Therefore, the increase in fetal MAP, HR and HRV that occurred with stimulation of peripheral thermoreceptors was the result of increased activity of the sympathetic nervous system. Alterations in efferent cardiac vagal tone were not involved in the cardiac response to cold.

DOI 10.1046/j.1440-1681.2000.03305.x
Citations Scopus - 7
Co-authors E Lumbers
2000 Gibson KJ, McMullen JR, Lumbers ER, 'Renal acid-base and sodium handling in hypoxia and subsequent mild metabolic acidosis in foetal sheep', Clinical and Experimental Pharmacology and Physiology, 27 67-73 (2000)

1. To measure the renal contribution to acid-base homeostasis during hypoxia (not associated with hypercapnia) and in response to the subsequent mild metabolic acidosis and to det... [more]

1. To measure the renal contribution to acid-base homeostasis during hypoxia (not associated with hypercapnia) and in response to the subsequent mild metabolic acidosis and to determine the effects of this hypoxia on the renal handling of sodium, studies were performed in six chronically catheterized foetal sheep (129-138 days gestation) before, during and for 1 h after a 2 h period of hypoxia. 2. Hypoxia was induced in the conscious ewe by infusing nitrogen into the trachea. Foetal arterial oxygen tension fell to 12.0 ± 0.6 mmHg (P < 0.001). Carbon dioxide tension fell during hypoxia (P < 0.001) and was still somewhat reduced in the recovery period (P < 0.005). Arterial Ph fell progressively to 7.19 ± 0.08 in the recovery period (P < 0.05). Plasma bicarbonate concentrations fell (P < 0.001) and lactate rose (P < 0.001). 3. Urinary pH and the excretion rates of bicarbonate, titratable acid, ammonium and net acid did not change during hypoxia. Ammonium excretion and, hence, generation of new bicarbonate increased in the recovery period (P < 0.05). 4. Renal sodium excretion progressively increased and was greatest after normoxia was restored (P < 0.05). This natriuresis was due to a fall in the reabsorption of sodium by the proximal tubule (P < 0.05). Proximal reabsorption of sodium was directly related to foetal Ph (P < 0.0001) and bicarbonate reabsorption (P < 0.001). 5. It was concluded that: (i) the foetal kidneys began to contribute to the maintenance of acid-base balance within the first hour of recovery from a 2 h episode of hypocapnic hypoxia, even though the acidosis was relatively mild; and (ii) a reduction in bicarbonate reabsorption was probably the most important factor that limited sodium reabsorption by the renal tubule during this experiment.

DOI 10.1046/j.1440-1681.2000.03207.x
Citations Scopus - 6
Co-authors E Lumbers
2000 Zhang DY, Lumbers ER, Simonetta G, Wu JJ, Owens JA, Robinson JS, McMillen IC, 'Effects of placental insufficiency on the ovine fetal renin-angiotensin system', EXPERIMENTAL PHYSIOLOGY, 85 79-84 (2000) [C1]
DOI 10.1111/j.1469-445X.2000.01939.x
Citations Scopus - 31Web of Science - 26
Co-authors Caroline Mcmillen, E Lumbers
2000 Lumbers ER, 'Fetal renal circulation', Advances in Organ Biology, 9 275-299 (2000)

This chapter details the development of the renal vasculature, the RAS, and the neural supply to the kidney. The sensitivity of the developing kidney to disruption of the activity... [more]

This chapter details the development of the renal vasculature, the RAS, and the neural supply to the kidney. The sensitivity of the developing kidney to disruption of the activity of the fetal RAS is described. The fetal kidney has a high RVR and a low RBF and GFR. The effects on RBF and GFR of the RSNs, vasoactive peptides, and endothelium-derived factors such as NO are described. There are several unique features about the fetal renal vascular responses. First, it appears that endothelin can mediate a vasodilator response in the fetal circulation through stimulation of NO production. Second, stimulation of RSNs after adrenoreceptor blockade causes renal vasodilation. © 2000.

Citations Scopus - 3
Co-authors E Lumbers
1999 McMullen JR, Gibson KJ, Lumbers ER, Burrell JH, Wu J, 'Interactions between AT1 and AT2 receptors in uterine arteries from pregnant ewes', European Journal of Pharmacology, 378 195-202 (1999)

This study was performed to investigate the roles of angiotensin receptors (AT 1 and AT 2 ) in the contractility of uterine arteries during normal pregnancy and after angiotensin... [more]

This study was performed to investigate the roles of angiotensin receptors (AT 1 and AT 2 ) in the contractility of uterine arteries during normal pregnancy and after angiotensin II levels have been elevated. Pregnant ewes were given intravenous infusions of saline for 24 h (control) or angiotensin II (30 ng kg -1 min -1 ) for 2 or 24 h. The contractile responses of uterine arterial rings to angiotensin II (4 µM) and antagonists were then examined in vitro. Most uterine arteries were relatively insensitive to the vasoconstrictor effects of angiotensin II. In rings from control ewes an angiotensin AT 2 antagonist enhanced (P < 0.05) the contractile responses to angiotensin II, suggesting that angiotensin AT 2 receptors inhibited the angiotensin AT 1 receptor mediated contractions. Uterine arterial rings from ewes given intravenous infusions of angiotensin II displayed greater (P < 0.05) contractile responses to angiotensin II in vitro compared to rings from control ewes. This was in part due to down regulation of angiotensin AT 2 receptors. Surprisingly, while performing these experiments a small number of ewes had uterine arteries which were 'hyperreactive' to angiotensin II (contractile responses 6-fold greater). These ewes also had abnormal renin angiotensin systems and had some features which are characteristic of those seen in preeclampsia. The 'hyperreactivity' of these arteries could only in part be explained by down regulation of angiotensin AT 2 receptors. It is concluded that in normal pregnancy angiotensin AT 2 receptors play a role in maintaining an adequate uterine blood flow for the fetus. When angiotensin II levels are elevated for a prolonged period this protective effect is lost partly because angiotensin AT 2 receptors are down regulated. Copyright (C) 1999 Elsevier Science B.V.

DOI 10.1016/S0014-2999(99)00454-9
Citations Scopus - 36
Co-authors E Lumbers
1999 Lumbers ER, Yu ZY, 'A method for determining baroreflex-mediated sympathetic and parasympathetic control of the heart in pregnant and non-pregnant sheep', Journal of Physiology, 515 555-566 (1999)

1. The cardiac baroreflex was measured in four non-pregnant and six pregnant ewes before and during ß-adrenoreceptor blockade with propranolol and before and during vagal blockad... [more]

1. The cardiac baroreflex was measured in four non-pregnant and six pregnant ewes before and during ß-adrenoreceptor blockade with propranolol and before and during vagal blockade with atropine. Arterial pressure was raised by phenylephrine and lowered by sodium nitroprusside. The relationships between mean arterial pressure (MAP) and heart rate (HR), between MAP and heart rate variability (HRV) measured as the coefficient of variation (c.v.) of the mean pulse interval (PI), and between MAP and HRV measured by power spectral analysis were determined. 2. The MAP-HR relationship showed that in pregnant ewes the gain of the cardiac baroreflex was reduced when compared with non-pregnant ewes. Threshold and saturation pressures were higher, maximum achievable HR was lower and there was a decrease in the operating range. 3. V-shaped relationships were obtained between MAP and HRV (measured as the c.v. of PI) and between MAP and power spectral density in the frequency range 0.04-0.08 Hz. Using selective autonomic blockade the negative, or downward, slope of the V shape was shown to be a measure of baroreceptor-induced, sympathetically mediated effects on HRV. The upward, or positive, slope of the V shape was a measure of baroreceptor-induced, vagally mediated effects. Similar results were also obtained from the cardiac power spectrum, but it was less sensitive. The MAP at which the two slopes intersected was the same as the resting MAP. 4. In pregnant ewes, the slope of the downward limb of the V-shaped relationship between HRV (when measured as the c.v. of PI) and MAP was less than in non-pregnant ewes. 5. The relationship between MAP and the coefficient of variation of the mean pulse interval can therefore be used to measure the degree to which baroreceptor-induced sympathetic and parasympathetic activity affects the heart. 6. The resting MAP is the pressure at which the net effect of these sympathetic and parasympathetic influences on the heart is at a minimum. Studies of both the MAP-HR and MAP-HRV relationships in pregnant and non-pregnant sheep show that in pregnant sheep, there is attenuation of baroreceptor-mediated sympathetic effects on the heart.

Citations Scopus - 23
Co-authors E Lumbers
1999 Dodic M, Peers A, Coghlan JP, May CN, Lumbers E, Yu ZY, Wintour EM, 'Altered cardiovascular haemodynamics and baroreceptor-heart rate reflex in adult sheep after prenatal exposure to dexamethasone', Clinical Science, 97 103-109 (1999)

Numerous epidemiological studies, together with mounting evidence from studies in animals, point to a correlation between an adverse intrauterine environment and the early onset o... [more]

Numerous epidemiological studies, together with mounting evidence from studies in animals, point to a correlation between an adverse intrauterine environment and the early onset of cardiovascular and metabolic diseases later in life. We were the first to show that sheep exposed to dexamethasone (0.28 mg·kg -1 ·day -1 for only 2 days) at the end of the first month of pregnancy (PTG1), but not those exposed at the end of the second month of pregnancy (PTG2), had a higher basal mean arterial pressure (MAP) 19 months after birth. In the present study we report the MAP, cardiovascular haemodynamics and baroreflex sensitivity in these animals at 40 months of age. MAP in the PTG1 group was significantly higher than in the control group (91 ± 1 mmHg and 81 ± 1 mmHg respectively; P < 0.001) and also when compared with the PTG2 group (82 ± 1 mmHg; P < 0.001). There was a significant increase in cardiac output in the PTG1 group compared with the control group (108 ± 2 and 96 ± 4 ml·min -1 ·kg -1 respectively; P < 0.05). The increase in cardiac output in the PTG1 group was due to an increase in stroke volume (1.82 ± 0.08 ml·kg -1 ·beat -1 , compared with 1.46 ± 0.06 ml·kg -1 ·beat -1 in the control group; P < 0.05), but not in heart rate. In the hypertensive group of animals (PTG1), there was a rightward shift of the baroreflex curve. In group PTG2 (the normotensive group of animals), a lower gain was found before and during propranolol treatment. The decrease in gain of the baroreflex was not associated with changes in heart rate range, suggesting an impairment in the central processing of the baroreceptor signals. Thus sheep fetuses exposed to dexamethasone for only 2 days at the end of the first month of gestation have high blood pressure (dependent upon the increase in cardiac output) and a reset of the baroreflex at 40 months of age. Animals that have received prenatal dexamethasone closer to mid-gestation, although normotensive with normal cardiac output, showed an altered baroreceptor-heart rate response.

DOI 10.1042/CS19980356
Citations Scopus - 68
Co-authors E Lumbers
1999 Burrell JH, Lumbers ER, Bernasconi C, 'Effects of ACTH-induced hypertension in the pregnant ewe', Journal of Cardiovascular Pharmacology, 34 818-823 (1999)

Adrenocorticotropic hormone (ACTH; 5 µg/kg/day) infused into 10 pregnant ewes (gestation age, 127-139 days) for 72 h caused an increase in arterial pressure within 1-2 h (p < 0... [more]

Adrenocorticotropic hormone (ACTH; 5 µg/kg/day) infused into 10 pregnant ewes (gestation age, 127-139 days) for 72 h caused an increase in arterial pressure within 1-2 h (p < 0.05), which was sustained for the rest of the experiment. Cardiac output was increased at 24 h (p < 0.05). Total peripheral resistance did not change. There were no changes in four pregnant ewes infused with 0.15 M saline at the same rate for 72 h. In ACTH-treated pregnant ewes, a relation between arterial pressure and plasma renin activity observed in nontreated pregnant ewes (r = 0.71; p = 0.0005) was no longer evident. Compared with nonsurgical pregnant ewes, total angiotensin II (Ang II)-receptor density in the uterine artery was decreased in ewes that had previously had surgery (p = 0.01.5) and further reduced in ACTH-treated ewes (p < 0.0005). This was due to a reduction in the AT2-receptor density, which was inversely related to plasma cortisol levels (r = 0.73; p < 0.03). AT 1 - receptor density and the affinities of the AT 1 and AT 2 receptors were unchanged. The correlation between plasma cortisol and AT 2 -receptor density in uterine blood vessels may partly explain why these receptors are downregulated after surgery.

DOI 10.1097/00005344-199912000-00008
Citations Scopus - 3
Co-authors E Lumbers
1999 Stevens AD, Lumbers ER, 'The effects of long-term infusions of angiotensin II into the pregnant ewe on uterine blood flow and on the fetus', Journal of Cardiovascular Pharmacology, 34 824-830 (1999)

The effects of intravenous (i.v.) infusions of 62.5 µg/h of angiotensin II (Ang II) on maternal arterial pressure (MMAP), cardiac output (CO), and uteroplacental blood flow (UPF)... [more]

The effects of intravenous (i.v.) infusions of 62.5 µg/h of angiotensin II (Ang II) on maternal arterial pressure (MMAP), cardiac output (CO), and uteroplacental blood flow (UPF) were studied in 11 chronically catheterized pregnant ewes and their fetuses. Over the first 4 h of infusion, MMAP (p < 0.01) increased and CO decreased (p < 0.05). UPF and fetal Po 2 , Pco 2 , and pH were unchanged. After 16-24 h, MMAP increased further (p < 0.05-p < 0.005); UPF decreased (p < 0.05), and vascular resistance increased (p < 0.05). Fetal arterial Po 2 decreased and Pco 2 increased (p < 0.001; p < 0.05). There were correlations between fetal arterial Po 2 and UPF (r = 0.6; p < 0.00005; n = 81), pH and UPF (r = 0.39; p < 0.0003; n = 81) and a negative correlation between Pco 2 and UPF (r = -0.5; p < 0.00005; n = 81). Infusions of 33 µg/h of noradrenaline initially caused a decrease in UPF. In the longer term, UPF was unchanged, as was UVR. There were no changes in fetal blood gases or pH, but there was a correlation between fetal arterial Po 2 and UPF (r = 0.48; p < 0.01; n = 27). The short-term effects of Ang II and noradrenaline on UPF and UVR are similar to effects reported previously. The finding that long-term infusions of Ang II caused a reduction in UPF and compromised fetal gas exchange was unexpected. Thus the protective effect of reduced vascular reactivity of the uteroplacental circulation to Ang II is only a transient phenomenon.

DOI 10.1097/00005344-199912000-00009
Citations Scopus - 4
Co-authors E Lumbers
1999 Lumbers ER, 'Angiotensin and aldosterone', Regulatory Peptides, 80 91-100 (1999)

The object of this review is to describe the role of the renin-angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin-ang... [more]

The object of this review is to describe the role of the renin-angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin-angiotensin (RAS) system, the activity of which is determined predominantly by control of renin secretion from the kidney and on the role of the intra-adrenal RAS. Angiotensin can bind to two types of G protein coupled receptors, the AT 1 and AT 2 receptors. Both receptors are found on cells from the zona glomerulosa, the site of aldosterone synthesis. Angiotensin II acting via the AT 1 receptor stimulates the synthesis of aldosterone at early and late steps in the pathway. Its effect on aldosterone is influenced by a number of other factors such as plasma potassium levels, sodium status, other peptides such as ANP and adrenomedullin and proadrenomedullin N-terminal peptide. All components of the RAS are found in the adrenal gland. The activity of this intra-adrenal RAS is unmasked and amplified in nephrectomised animals. Aldosterone controls sodium transport across epithelial cells, but recently novel effects on the heart have been described. Copyright (C) 1999.

DOI 10.1016/S0167-0115(99)00026-9
Citations Scopus - 74
Co-authors E Lumbers
1999 Gibson KJ, Lumbers ER, 'Effects of bilateral nephrectomy and angiotensin II replacement on body fluids in foetal sheep', Clinical and Experimental Pharmacology and Physiology, 26 765-773 (1999)

1. To determine the importance of the kidneys in maintaining the normal volume and composition of foetal body fluids, measurements were made in 11 chronically catheterized foetuse... [more]

1. To determine the importance of the kidneys in maintaining the normal volume and composition of foetal body fluids, measurements were made in 11 chronically catheterized foetuses (123-136 days) that had been bilaterally nephrectomized at least 5 days previously and compared with 10 intact foetuses (121-133 days). 2. The nephrectomized foetuses had reduced extracellular (ECV), blood, plasma and interstitial volumes per kg foetal weight (P < 0.005), reduced plasma chloride levels (P < 0.001) and were acidaemic, hypoxaemic and hypercapnaemic (P < 0.05) compared with intact foetuses. They also had reduced lung liquid production (P < 0.05) and reduced lung liquid sodium and osmolality levels (P < 0.05). Their arterial pressure was more variable between foetuses (P < 0.005) and was directly related to ECV/kg (P = 0.013). 3. To determine which of these changes were due to absence of the foetal renin-angiotensin system, seven chronically catheterized nephrectomized foetal sheep (124-132 days) were infused with replacement doses of angiotensin (Ang)II (1.5 µg/kg per h) for 3 days. Six nephrectomized foetuses were infused with 0.15 mol/L saline. 4. The AngII infusion was non-pressor. It prevented the fall in ECV that occurred in the control group (P < 0.05) and foetal plasma chloride concentration rose (P < 0.05). Blood gas status and lung liquid production rate did not change, but lung liquid sodium concentration fell (P < 0.05) and potassium concentration rose (P < 0.05). 5. Bolus injections of AngII (0.3-5 µg) were given to assess vascular sensitivity to AngII. This was not altered by either nephrectomy or AngII replacement. 6. It is concluded that the foetal kidneys are important for the maintenance of the normal volume and composition of foetal body fluids. Angiotensin II, perhaps because it promotes fluid transfer across the placenta, helps maintain foetal ECV and plasma chloride levels.

DOI 10.1046/j.1440-1681.1999.03127.x
Citations Scopus - 9
Co-authors E Lumbers
1998 Lumbers ER, Bernasconi C, Burrell JH, 'Effects of infusions of ACTH in the chronically catheterized pregnant ewe and her fetus.', The American journal of physiology, 274 R445-R452 (1998)
Co-authors E Lumbers
1998 McMullen JR, Gibson KJ, Lumbers ER, 'Effects of intravenous infusions of noradrenaline on renal function in chronically catheterised fetal sheep', Biology of the Neonate, 73 254-263 (1998)

To determine the effects of circulating noradrenaline on fetal renal function noradrenaline was infused intravenously into 7 chronically catheterised fetal sheep (127-138 days) at... [more]

To determine the effects of circulating noradrenaline on fetal renal function noradrenaline was infused intravenously into 7 chronically catheterised fetal sheep (127-138 days) at a dose (1 µg/kg/min) which resulted in plasma levels similar to those which occur during hypoxia. Fetal mean arterial pressure increased by approximately 14 mmHg (p < 0.001) and haematocrit rose (p < 0.005). Glomerular filtration rate rose from 3.85 ± 0.47 (SEM) to 4.70 ± 0.50 ml/min (p < 0.05) during the first hour and fractional reabsorption of sodium by the proximal tubule fell (p < 0.05) during the second hour. Urine flow rate increased from 0.61 ± 0.13 to 1.18 ± 0.24 ml/min (p < 0.001) and osmolar excretion increased from 78 ± 15 to 153 ± 36 µosm/min (p < 0.005). By contrast lung liquid flow fell (p < 0.05), but the increase in urine flow was much greater than the decline in lung liquid. These findings suggest that during hypoxia, noradrenaline may play an important role in the maintenance of urine flow and consequently amniotic fluid volume and, as suggested by others, in the distribution of fluid between the vascular and interstitial compartments.

DOI 10.1159/000013984
Citations Scopus - 2
Co-authors E Lumbers
1998 Yu ZY, Lumbers ER, Gibson KJ, Stevens AD, 'Effects of hypoxaemia on foetal heart rate, variability and cardiac rhythm', Clinical and Experimental Pharmacology and Physiology, 25 577-584 (1998)

1. Experiments were carried out in 30 chronically catheterized foetal sheep (128-144 days; term 150 days) and in seven of these foetuses before, during and after acute hypoxaemia.... [more]

1. Experiments were carried out in 30 chronically catheterized foetal sheep (128-144 days; term 150 days) and in seven of these foetuses before, during and after acute hypoxaemia. The extent to which changes in sympathoadrenal activity and cardiac vagal activity affected the foetal cardiac response to hypoxaemia was measured. Three measurements were used: foetal heart rate (FHR), heart rate variability (HRV; measured as the coefficient of variation in pulse interval) and power spectral density (PSD; measured over the frequency ranges of 0.04-1.3 Hz). Cardiac vagal activity was blocked by atropine, ß-andrenoceptor activity was blocked by propranolol. 2. Under normoxaemic conditions, cardiac vagal blockade caused a rise in mean arterial pressure MAP; P < 0.001), an increase in FHR (P < 0.001), a decrease in HRV (P < 0.001) and a decrease in PSD (P < 0.001). ß-Adrenoceptor blockade caused a rise in MAP (P < 0.001), a fall in FHR (P < 0.01), a decrease in HRV (P < 0.001) but no change in PSD. 3. During mild hypoxaemia (PO 2 = 12-14.5 mmHg) and moderate hypoxaemia (PO 2 = 10-11.9 mmHg), foetal MAP (P < 0.001, P < 0.001), HRV (P < 0.01, P < 0.001) and PSD in the frequency range 0.04-0.45 Hz increased (P < 0.05-P < 0.001). Foetal heart rate decreased when foetuses became moderately hypoxaemic (P < 0.001). 4. After cardiac vagal blockade, hypoxaemia was associated with an increase in FHR compared with non-blocked hypoxaemic foetuses (P < 0.01, P < 0.001). The increase in HRV was abolished (P < 0.001, P < 0.001) as was the increase in PSD (P < 0.01-P < 0.001). 5. After ß-adrenoceptor blockade, the bradycardia that occurred during hypoxaemia was enhanced (P < 0.01, P < 0.05), the increase in HRV was not affected and neither was the increase in PSD. 6. As FHR and HRV of normoxaemic foetal sheep were affected both by atropine and propranolol, it would seem that both cardiac vagal and sympathoadrenal activity modulate the foetal heart under resting conditions. The lack of any effect of ß-adrenoceptor blockade on PSD under these conditions suggests that power spectral analysis (PSA) is not as sensitive as the other two methods in detecting sympathetically mediated modulation of the heart. 7. Because the hypoxaemia induced bradycardia and increase in HRV and in PSD were abolished by atropine (P < 0.01-P < 0.001), it is concluded that during hypoxaemia foetal HRV is mainly modulated by changes in cardiac vagal tone. Propranolol had no effect on foetal HRV, although it reduced it under normoxaemic conditions; therefore, it is concluded that cardiac sympathetic neural activity was not increased in acute hypoxaemia uncomplicated by acidosis. However, there was strong evidence of increased sympathoadrenal tone on the foetal heart in hypoxaemia, that is, there was a rise in FHR in hypoxaemic atropinized foetuses and a greater fall in FHR in ß-adrenoceptor blocked hypoxaemic foetuses. Therefore, this increased sympathetic influence on the foetal heart during hypoxaemia must be predominantly the result of increased adrenomedullary secretion of catecholamines. 8. Maintenance of foetal cardiac output depends on the chronotropic and ionotropic effects of catecholamines. Therefore, this adrenomedullary influence on the foetal heart during hypoxaemia is important to offset the opposing effects of increased cardiac vagal tone.

Citations Scopus - 27
Co-authors E Lumbers
1998 Lumbers ER, Bernasconi C, Burrell JH, 'Effects of infusions of ACTH in the chronically catheterized pregnant ewe and her fetus', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 274 (1998)

To study the effects of elevated maternal levels of adrenocorticotropic hormone (ACTH) on the fetus, nine chronically catheterized pregnant ewes (132 ± 0.9 days of gestation) wer... [more]

To study the effects of elevated maternal levels of adrenocorticotropic hormone (ACTH) on the fetus, nine chronically catheterized pregnant ewes (132 ± 0.9 days of gestation) were infused intravenously for 3 days with Synacthen (5 µg · kg -1 · day -1 ). Four ewes were given 0.15 M saline intravenously over the same period. ACTH induced hypertension in the ewe. Mean arterial pressure (MAP) increased from 101 ± 4.4 to 114 ± 3.9 mmHg at 48 h (P < 0.05); cardiac output increased from 8.6 ± 0.5 to 10.4 ± 1.0 1/min after 24 h (P < 0.05). Within 2-4 h, maternal cortisol levels increased from 24.6 ± 6.3 to 287 ± 30 nM (P < 0.05) and remained high. Fetal plasma cortisol levels increased from 20 ± 4.5 to 60 ± 4.5 nM (P < 0.05) within 2- 4 h and then increased further. Fetal MAP was increased at 24 h. There was no effect on fetal blood gases or pH. Ewes became hyperglycemic and lactacidemic by 24 h (P < 0.05), and the fetuses were also hyperglycemic and lactacidemic (P < 0.05) at this time. There were no changes in fetuses carried by saline- infused ewes. Both ewes and fetuses had raised plasma osmolalities and, since hematocrit fell, retained fluid. Ewes became hypokalemic; the fetuses did not, but there was an increase in fetal K excretion. Thus ACTH-induced hypertension in the ewe had minimal effects on fetal MAP, fetal blood gas status, and pH. The fetus, however, did show many of the other effects of maternal glucocorticoid and mineralocorticoid excess, partly because its cortisol levels were increased but also as a consequence of metabolic and endocrine changes in the ewe.

Citations Scopus - 4
Co-authors E Lumbers
1998 Segar JL, Lumbers ER, Nuyt AM, Smith OJ, Robillard JE, 'Effect of antenatal glucocorticoids on sympathetic nerve activity at birth in preterm sheep', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 274 (1998)

Renal sympathetic nerve activity (RSNA) increases rapidly after delivery of term fetal sheep and parallels the rise in heart rate (HR) and arterial pressure. To examine the RSNA r... [more]

Renal sympathetic nerve activity (RSNA) increases rapidly after delivery of term fetal sheep and parallels the rise in heart rate (HR) and arterial pressure. To examine the RSNA response at birth in immature lambs, experiments were performed in chronically instrumented preterm fetal sheep (118- to 125-day gestation, term 145 days) before and afar delivery by cesarean section. HR remained unchanged from fetal values at 1 and 4 h after birth, whereas mean arterial blood pressure (MABP) decreased significantly (P < 0.05) by 4 h after delivery. RSNA significantly decreased after premature birth in all animals studied (n = 6), achieving only 39 ± 17% of fetal RSNA (P < 0.05; all results are mean ± SE). Because cardiovascular function after premature birth is improved by the use of antenatal corticosteroids, we also tested the hypothesis that corticosteroid administration would evoke a more pronounced sympathetic response in prematurely delivered lambs (n = 7, 118- to 125-day gestation). After maternal administration of dexamethasone (5 mg im, 48 and 24 h before delivery), RSNA increased after birth in six of seven fetuses to 166 ± 32% of the fetal RSNA value. Dexamethasone treatment also decreased the sensitivity of baroreflex-mediated changes in HR in response to increases in MABP. Because the sympathetic response at birth is depressed in preterm compared with term lambs, we performed an additional study (n = 8) to determine if immature sheep are capable of mounting a sympathetic response to cold. In utero cooling produced rapid and sustained increases in MABP (20 ± 4%), HR (26 ± 6%), and RSNA (282 ± 72%) (all P < 0.05), consistent with a generalized sympathoexcitation. These results suggest that sympathoexcitation is absent after premature delivery despite the presence of functional descending autonomic pathways. Furthermore, exogenous corticosteroids appear to have a maturational effect on the sympathetic response at birth, which may be one mechanism by which maternal steroid administration improves postnatal cardiovascular homeostasis.

Citations Scopus - 50
Co-authors E Lumbers
1998 Zhang DY, Lumbers ER, Wu JJ, 'Gestational changes in fetal renal and hepatic angiotensinogen mRNA and protein', Reproduction, Fertility and Development, 10 399-404 (1998)

The aim of the study was to determine the amount of angiotensinogen expression and its protein product in fetal sheep liver and kidney in the last third of gestation. Angiotensino... [more]

The aim of the study was to determine the amount of angiotensinogen expression and its protein product in fetal sheep liver and kidney in the last third of gestation. Angiotensinogen mRNA was measured by RNase protection assay and its protein levels were measured by radioimmunoassay. Levels were measured at 80, 95, 111, 125 and 139 days. Angiotensinogen mRNA was present in all fetal liver and kidney samples tested. The ratio of hepatic angiotensinogen mRNA/18 S rRNA increased by 100% (P < 0.001) and angiotensinogen levels increased by 33% (P < 0.001) in fetal sheep from 80 to 139 d. Over the same period the ratio of renal angiotensinogen mRNA/18 S rRNA increased by 170% (P < 0.001) and renal angiotensinogen protein increased by 41% (P < 0.001). The levels of angiotensinogen mRNA and its protein in the adult kidney were less than in kidneys of 139 d old fetuses (P < 0.01). There was a direct relationship between levels of angiotensinogen mRNA and its protein in the liver (r = 0.53, P < 0.01, n = 25) and in the kidney (r = 0.75, P < 0.0001, n = 24). These findings demonstrate that there is a significant increase in both hepatic and renal angiotensinogen gene expression in the last third of gestation in the fetal sheep and that this increase is associated with an increase of angiotensinogen levels in both tissues. This increase in angiotensinogen in late gestation could influence the activity of both the intrarenal and circulating renin angiotensin systems.

DOI 10.1071/RD98063
Citations Scopus - 4
Co-authors E Lumbers
1997 Gibson KJ, Lumbers ER, 'Ovine fetal cardiovascular, renal, and fluid balance responses to 3 days of high arginine vasopressin levels', American Journal of Physiology, 272 (1997)

-To determine the effects of sustained high levels of arginine vasopressin (AVP) on the fetus and whether these effects were the same as those found during acute infusion of AVP, ... [more]

-To determine the effects of sustained high levels of arginine vasopressin (AVP) on the fetus and whether these effects were the same as those found during acute infusion of AVP, chronically catheterized fetal sheep aged 121-136 days were infused for 3 days with either AVP (45 mU·kg -1 - h -1 ) or saline. The bradycardia, acidemia, and failure of glomerulotubular balance that occurred with acute AVP infusion were reversed by day 3 of AVP (P < 0.005) and the acute rise in arterial pressure was attenuated (P < 0.005). By contrast, the rise in the glomerular filtration rate was sustained (P < 0.005) and urinary osmolality increased further to 426 ± 30 mosmol/kg (P < 0.01). Although placental blood flow did not change acutely with AVP, it had fallen by day 3 (P < 0.01). In addition, with AVP but not saline extracellular volume fell from 588 ±28 to 493 ±29 ml/kg (P < 0.002) and the plasma/interstitial volume ratio rose from 0.18 ±0.01 to 0.21 ±0.01 (P = 0.001). These findings suggest that although release of AVP may be beneficial in acute stress in utero, sustained high levels may be detrimental to fetal health and sodium balance. 1 Copyright ö1997 the American Physiological Society.

Citations Scopus - 1
Co-authors E Lumbers
1997 Gibson KJ, Lumbers ER, 'Ovine fetal cardiovascular, renal, and fluid balance responses to 3 days of high arginine vasopressin levels.', The American journal of physiology, 272 R1069-R1076 (1997)
Co-authors E Lumbers
1997 Burrell JH, Lumbers ER, 'Angiotensin receptor subtypes in the uterine artery during ovine pregnancy', European Journal of Pharmacology, 330 257-267 (1997)

This study was undertaken to determine if changes in receptor density or affinity could account for the reduced vascular sensitivity to angiotensin II seen during pregnancy. Angio... [more]

This study was undertaken to determine if changes in receptor density or affinity could account for the reduced vascular sensitivity to angiotensin II seen during pregnancy. Angiotensin receptor subtypes in the uterine arteries of non-pregnant, pregnant and postpartum ewes were investigated using saturation and competition receptor binding techniques with the specific receptor antagonists, losartan (DuP-753) and PD-123319 (S)1-[[4-(dimethylamino)-3-methylphenyl]-methyl] -5-(diphenylacetyl)-4,5,6,7 -tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid, ditrifluoroacetate, monohydrate). Receptor density and affinity of total angiotensin receptors, as well as the angiotensin AT 1 and AT 2 receptor subtypes in uterine arteries were compared with those in the mesenteric artery and aorta. The uterine artery contains both AT 1 and AT 2 receptor subtypes, whereas the mesenteric artery and aorta contain primarily the AT 1 receptor subtype. In uterine arteries from pregnant sheep, angiotensin receptor density was increased because AT 2 receptors were increased. AT 1 receptor density was not altered. This change was not seen in the aorta. In the uterine artery, receptor affinity for [Sar 1 ,Ile 8 ]angiotensin II decreased in mid-gestation (IC 50 7.7 ± 1.2 x 10 -9 M) compared with non-pregnant ewes (IC 50 3.0 ± 0.6 x 10 -9 M, P = 0.006), and there was decreased affinity of angiotensin AT 1 receptors for losartan during pregnancy (IC 50 2.8 ± 1.0 x 10 -4 M) compared with non-pregnant ewes (IC 50 2.2 ± 1.3 x 10 -6 M, P = 0.025). Our results show changes in the density and affinity of the angiotensin receptor subtypes in the uterine artery which could explain its reduced responsiveness to circulating angiotensin II during pregnancy.

DOI 10.1016/S0014-2999(97)00167-2
Citations Scopus - 39
Co-authors E Lumbers
1997 Lumbers ER, 'Effects of drugs on uteroplacental blood flow and the health of the foetus', Clinical and Experimental Pharmacology and Physiology, 24 864-868 (1997)

1. The placental vascular bed is normally fully dilated. Therefore, changes in vascular resistance elsewhere in the body can affect uteroplacental blood flow (UBF). For example, a... [more]

1. The placental vascular bed is normally fully dilated. Therefore, changes in vascular resistance elsewhere in the body can affect uteroplacental blood flow (UBF). For example, antihypertensive drugs, such as diazoxide, hydralazine and the angiotensin-converting enzyme inhibitor captopril, cause falls in arterial pressure and, hence, in UBF. 2. Angiotensin II (AngII), prostacyclin and nitric oxide (NO) all influence uteroplacental vascular tone. Angiotensin II in a pharmacological dose (62.5 µg/h) had a biphasic effect on UBF in the sheep. Initially, there was a rise in UBF as pressure rose; however, by 16-24 h, UBF had fallen. The AngII-induced fall in UBF caused severe foetal hypoxia and hypercapnia. 3. Prostacyclin may protect the uteroplacental circulation from vasoconstrictors such as AngII, as the vasoconstrictor effect of AngII in the uteroplacental circulation is enhanced following indomethacin. 4. Oestrogen-induced uterine artery vasodilation is nitrergic dependent. As well, nitrergic nerves alter the responsiveness of pregnant uterine arteries to noradrenaline. 5. Thus, both systemic and local factors are important in the control of UBF and in promoting foetal health and growth.

Citations Scopus - 7
Co-authors E Lumbers
1997 Lumbers ER, Burrell JH, Stevens AD, Weir BA, 'Effects of one-clip, one-kidney hypertension in chronically catheterized pregnant ewes', Clinical and Experimental Pharmacology and Physiology, 24 336-343 (1997)

1. Hypertension secondary to renal disease was studied in non-pregnant and pregnant ewes to determine whether there were any changes in arterial pressure and the distribution of c... [more]

1. Hypertension secondary to renal disease was studied in non-pregnant and pregnant ewes to determine whether there were any changes in arterial pressure and the distribution of cardiac output and, in particular, whether uteroplacental blood flow was affected. 2. In six non-pregnant, chronically catheterized, uninephrectomized ewes, a reduction in renal blood flow (RBF) to 40-50% of control caused hypertension within 3 h. This was maintained for as long as RBF was reduced (72 h) and returned to control 24 h after the occluder around the renal artery was released. When this experiment was repeated in 16 uninephrectomized pregnant ewes (118-134 days gestation) hypertension occurred within 3 h and was sustained for as long as RBF was reduced (between 24 and 72 h). Arterial pressure returned to control within 24-72 h of restoring RBF. 3. Compared with non-pregnant ewes, pregnant ewes had similar arterial pressures, higher cardiac outputs (CO; P < 0.001) and heart rates (HR; P < 0.001), lower total peripheral resistances (TPR; P < 0.001) and similar blood flows to brain, ovary, pancreas, kidney and spleen. Splenic vascular resistance (VR) was greater (P = 0.006), gut blood flow was greater (P < 0.05) and gut VR was less (P < 0.05). Myoendometrial blood flow/g was greater (P < 0.005) and myoendometrial VR was less (P = 0.006). 4. In pregnant sheep with renal clip hypertension, there was no change in CO and H R, but TPR increased (P < 0.01), as did plasma renin activity. Gut, brain, pancreatic and myoendometrial VR were increased as long as RBF was reduced; in addition, myoendometrial VR remained high for the rest of the experiment. Placental blood flow was unchanged at 3h; 24-72h later it was reduced (P < 0.05) and remained low. Placental VR was increased 24-72 h after RBF was restored when ewes were again normotensive. 5. Thus, one-clip, one-kidney renal hypertension in the pregnant ewe was due to increased TPR associated with a fall in uteroplacental blood flow that persisted even when RBF was restored and ewes were normotensive. This reduction in uteroplacental blood flow could account fur the high foetal morbidity and mortality that occurs in pregnant women with renovascular hypertension.

Citations Scopus - 8
Co-authors E Lumbers
1997 Gibson KJ, Lumbers ER, 'Ovine fetal cardiovascular, renal, and fluid balance responses to 3 days of high arginine vasopressin levels', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 272 (1997)

To determine the effects of sustained high levels of arginine vasopressin (AVP) on the fetus and whether these effects were the same as those found during acute infusion of AVP, c... [more]

To determine the effects of sustained high levels of arginine vasopressin (AVP) on the fetus and whether these effects were the same as those found during acute infusion of AVP, chronically catheterized fetal sheep aged 121-136 days were infused for 3 days with either AVP (45 mU · kg -1 · h -1 ) or saline. The bradycardia, acidemia, and failure of glomerulotubular balance that occurred with acute AVP infusion were reversed by day 3 of AVP (P < 0.005) and the acute rise in arterial pressure was attenuated (P < 0.005). By contrast, the rise in the glomerular filtration rate was sustained (P < 0.005) and urinary osmolality increased further to 426 ± 30 mosmol/kg (P < 0.01). Although placental blood flow did not change acutely with AVP, it had fallen by day 3 (P < 0.01). In addition, with AVP but not saline extracellular volume fell from 588 ± 28 to 493 ± 29 ml/kg (P < 0.002) and the plasma/interstitial volume ratio rose from 0.18 ± 0.01 to 0.21 ± 0.01 (P = 0.001). These findings suggest that although release of AVP may be beneficial in acute stress in utero, sustained high levels may be detrimental to fetal health and sodium balance.

Citations Scopus - 5
Co-authors E Lumbers
1997 Gibson KJ, Lumbers ER, 'Ovine fetal cardiovascular, renal, and fluid balance responses to 3 days of high arginine vasopressin levels', American Journal of Physiology - Heart and Circulatory Physiology, 41 (1997)

Tb determine the effects of sustained hieh levels of arginine vasopressin (AVP) on the fetus and whether these effects were the same as those found during acute infusion of AVP, c... [more]

Tb determine the effects of sustained hieh levels of arginine vasopressin (AVP) on the fetus and whether these effects were the same as those found during acute infusion of AVP, chronically catheterized fetal sheep aged 121-136 days were infused for 3 days with either AVP (45 mU-kg"1"1) or saline. The bradycardia, acidemia, and failure of glomerulotubular balance that occurred with acute AVP infusion were reversed by day 3 of AVP (P < 0.005) and the acute rise in arterial pressure was attenuated (P < 0.005). By contrast, the rise in the glomerular filtration rate was sustained (P < 0.005) and urinary osmolality increased further to 426 ± 30 mosmol/kg (P < 0.01). Although placental blood flow did not change acutely with AVP, it had fallen by Jay 3 (P < 0.01). In addition, with AVP but not saline extracellular volume fell from 588 ±28 to 493 ±29 ml/kg (P < 0.002) and the plasma/interstitial volume ratio rose from 0.18 ±0.01 to 0.21 ±0.01 (P = 0.001). These findings suggest that although release of AVP may be beneficial in acute stress in utero, sustained high levels may be detrimental to fetal health and sodium balance. fetal stress; placental blood flow; arterial pressure; sodium Copyright ©1997 the American Physiological Society.

Citations Scopus - 2
Co-authors E Lumbers
1996 Lumbers ER, Burrell JH, Stevens AD, Bernasconi C, 'Responses of fetal sheep to reduced maternal renal blood flow and maternal hypertension.', The American journal of physiology, 271 R1691-R1700 (1996)
Co-authors E Lumbers
1996 Lumbers ER, Bernasconi C, Burrell JH, 'Effects of inhibition of the maternal renin-angiotensin system on maternal and fetal responses to drainage of fetal fluids', Canadian Journal of Physiology and Pharmacology, 74 973-982 (1996)

To find out which of the effects of angiotensin converting enzyme (ACE) inhibitors on the fetus are due to their actions in the mother and which are direct effects due to blockade... [more]

To find out which of the effects of angiotensin converting enzyme (ACE) inhibitors on the fetus are due to their actions in the mother and which are direct effects due to blockade of the fetal renin-angiotensin system, enalapril (150 mg twice daily i.v.), which does not readily cross the sheep placenta, was given for 3 days to nine chronically catheterized pregnant ewes, 5 days after fetal urine and lung liquid had been continuously drained and while drainage of these fetal fluids continued. Drainage of fetal fluids was carried out so that a net sodium deficit would be incurred, and the dependency of the ewe on the activity of her renin-angiotensin system (RAS) for maintenance of her arterial pressure and fluid and electrolyte balance would be increased. During drainage of fetal fluids ewes drank more and increased their net water balance (p < 0.025). With enalapril, ewes became hypotensive (p < 0.005), but heart rate did not change. Maternal plasma potassium (K) levels increased (p < 0.05) and the plasma sodium to potassium ratio (Na:K) decreased (p < 0.005). Enalapril did not reduce maternal water intake nor change her urine output. After 5 days of drainage, fetal plasma K levels (p < 0.05) were higher and plasma Na:K (p < 0.025) was lower. After maternal enalapril, lung liquid flow and electrolyte excretion were transiently reduced (p < 0.05). Fetal plasma K levels increased further (p < 0.025) and plasma Na:K ratio decreased (p < 0.025 -p < 0.01). Fetal arterial PO 2 was reduced 2 h after enalapril (p < 0.005) and was low on the last 2 days of treatment. Although fetal fractional reabsorption of K fell (p < 0.01) by the last day of enalapril treatment, the increase in fetal K excretion was not significant, because by this time sufficient enalapril was present in the fetal circulation to reduce glomerular filtration rate (GFR, p < 0.025 -p < 0.001). It is concluded that the toxicity of ACE inhibitors may be related to those effects in the ewe that lead to reduced fetal arterial oxygen levels and increased fetal plasma K levels. In the latter case it is postulated that inhibition of the maternal RAS may leave ewe and fetus deficient in aldosterone, leading to the rise in K levels. Thus the toxic effects of ACE inhibitors can be mediated through their effects on the mother, but their ability to cause fetal renal failure and oligohydramnios is due to their direct effects on the fetal RAS.

DOI 10.1139/cjpp-74-8-973
Citations Scopus - 8
Co-authors E Lumbers
1996 Gibson KJ, Lumbers ER, 'The effects of continuous drainage of fetal fluids on salt and water balance in fetal sheep', Journal of Physiology, 494 443-450 (1996)

1. In nine chronically catheterized fetuses in which all lung liquid was drained continuously from the time of surgery, the effects of continuous drainage of fetal urine for 1 wee... [more]

1. In nine chronically catheterized fetuses in which all lung liquid was drained continuously from the time of surgery, the effects of continuous drainage of fetal urine for 1 week on fetal renal function, lung liquid production and salt and water balance were studied. Fetal well-being, as judged by fetal growth, urinary osmolality, blood gas status, arterial pressure and heart rate, was not adversely affected by urine drainage. The ewes, however, drank more water when fetal urine was drained. Thus, fetal plasma and urinary osmolalities declined (P < 0.025 and P < 0.05). 2. Fetal glomerular filtration rate fell from 75 ± 4 ml kg -1 h -1 (± S.E.M., n = 9) before drainage to 54 ± 7 ml kg -1 h -1 after drainage (n= 7; P < 0.005), and fetal renal sodium excretion also declined (P < 0.05). However, the excretion of sodium in lung liquid did not decrease and the fetal renin-angiotensin system was not activated. Petal extracellular volume (561 ± 44 ml kg -1 , n = 7) and the calculated net sodium transfer (0.76 mmol kg -1 h -1 , n = 6) and fluid transfer (15 ± 2 ml kg -1 h -1 , n = 8) to the fetus did not change. 3. It is concluded that overall fetal salt and water balance were maintained when all fetal urine and lung liquid were drained from fetal sheep in late gestation. Since drainage of urine and lung: liquid considerably reduced the amniotic and allantoic fluids, transfer across the placenta and extraplacental membranes was able to compensate for the absence of these fluids. In response to the loss of sodium during: drainage, fetal renal sodium conservation was about 11% of the total sodium conservation by the materno-fetal unit.

Citations Scopus - 11
Co-authors E Lumbers
1996 Zhang DYL, Lumbers ER, Simonetta G, 'Changes in renal renin gene expression in fetal sheep', CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 23 682-684 (1996)
DOI 10.1111/j.1440-1681.1996.tb01758.x
Citations Scopus - 9Web of Science - 10
Co-authors E Lumbers
1996 Stevenson KM, Gibson KJ, Lumbers ER, 'Effects of losartan on the cardiovascular system, renal haemodynamics and function and lung liquid flow in fetal sheep', Clinical and Experimental Pharmacology and Physiology, 23 125-133 (1996)

The angiotensin type 1 (AT 1 ) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125-132 days gestation). Losartan... [more]

The angiotensin type 1 (AT 1 ) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125-132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 µg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1 h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2 h. Maternal pressor responses to 5 µg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change. Fetal haematocrit increased (P < 0.05), fetal PO 2 decreased (P < 0.01), PCO 2 did not change and pH decreased (P < 0.01), as did plasma bicarbonate levels (P < 0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P < 0.01) and an increase in blood flow (P < 0.05). Glomerular filtration rate decreased (P < 0.05); thus, filtration fraction decreased (P < 0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P < 0.01) and became negative. Urine flow decreased (P < 0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium: potassium ratio decreased (P < 0.05). There was a decrease in lung liquid flow (P < 0.05) following losartan. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT 1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.

Citations Scopus - 33
Co-authors E Lumbers
1996 Lumbers ER, Burrell JH, Stevens AD, Bernasconi C, 'Responses of fetal sheep to reduced maternal renal blood flow and maternal hypertension', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 271 (1996)

In 16 chronically catheterized fetal sheep the effects of reducing and restoring maternal renal blood flow (RBF) and thus inducing and reversing hypertension were studied in unine... [more]

In 16 chronically catheterized fetal sheep the effects of reducing and restoring maternal renal blood flow (RBF) and thus inducing and reversing hypertension were studied in uninephrectomized pregnant ewes; controls were 3 fetuses that were carried by uninephrectomized ewes in which RBF was not reduced and that did not become hypertensive. Within 24-72 h of maternal RBF reduction, fetal arterial PO 2 had fallen (P < 0.001) and PCO 2 had increased (P < 0.025); fetal arterial pressure also increased (P < 0.005). These effects persisted, despite restoration of maternal RBF and reversal of maternal hypertension. Within 24-72 h of reduction of maternal RBF, fetal urine flow had increased (P < 0.005), and it remained elevated over the first 3 h after RBF was restored; 24-72 h later it was lower (P < 0.025) and returned to control levels. The excretion of sodium, potassium, and chloride showed a similar increase when maternal RBF was reduced (P < 0.001), with return to control values 24-72 h after RBF had been restored. Fetal glomerular filtration rate did not change; thus the natriuresis and diuresis that occurred were due to reduced tubular solute and water reabsorption (P < 0.025). These changes in fetal renal function may be related, in part, to changes in fetal PO 2 and PCO 2 , but they are most likely due to reduced maternal renal function due to the restriction in maternal RBF, inasmuch as they were reversed when RBF was restored.

Citations Scopus - 8
Co-authors E Lumbers
1995 Lumbers ER, 'FUNCTIONS OF THE RENIN-ANGIOTENSIN SYSTEM DURING DEVELOPMENT', Clinical and Experimental Pharmacology and Physiology, 22 499-505 (1995)

1. From studies in chronically catheterized fetal sheep and other species, it can be shown that the renin-angiotensin system (RAS) is active during intra-uterine life. Levels of a... [more]

1. From studies in chronically catheterized fetal sheep and other species, it can be shown that the renin-angiotensin system (RAS) is active during intra-uterine life. Levels of angiotensin II (AII) in fetal sheep are similar to maternal. 2. The fetal RAS plays a role in maintenance of arterial pressure. The extent to which it does so depends on the level of activity of the system. 3. The distribution of renin within the fetal rat kidney is much more widespread than in the adult. The fetal kidney, like other vascular beds has high levels of the AT 2 angiotensin receptor subtype. With maturation the proportion of the AT 1 receptor subtype increases. 4. Blockade of the fetal RAS with angiotensin converting enzyme (ACE) inhibitors or with the non-peptide AII antagonist (losartan) caused a fall in fetal glomerular filtration rate (GFR) and a rise in renal blood flow (RBF). AII reverses the fall in GFR even though RBF decreases. 5. The fraction of the filtered sodium load reabsorbed by the proximal tubule was not affected when the fetal RAS was blocked by captopril or losartan. High doses of infused AII had no effect on renal reabsorption of sodium, in the short term, but in the long term depressed fractional proximal reabsorption. 6. Only in high doses does AII stimulate the secretion of aldosterone from the fetal adrenal. 7. Since the fetal RAS is responsible for maintenance of GFR and physiological levels of AII do not stimulate either proximal tubular sodium reabsorption nor aldosterone secretion, it is proposed that during intra-uterine life the fetal RAS maintains the renal excretion of sodium and water into the amniotic cavity, thus ensuring an adequate volume of amniotic fluid for normal growth and development. Copyright © 1995, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1440-1681.1995.tb02057.x
Citations Scopus - 68
Co-authors E Lumbers
1995 Lumbers ER, Moore RS, Stevens AD, 'Effects of changes in colloid osmotic pressure on excretion of sodium by the ovine fetal kidney', Reproduction, Fertility and Development, 7 1321-1327 (1995)

To find out if the gestation-dependent increase in fetal oncotic pressure is responsible for the gestation-dependent increase in the capacity of the fetal proximal tubule to reabs... [more]

To find out if the gestation-dependent increase in fetal oncotic pressure is responsible for the gestation-dependent increase in the capacity of the fetal proximal tubule to reabsorb sodium, the effects on renal function of increases in oncotic pressure were studied in 8 volume-expanded chronically catheterized fetal sheep aged 128 ±3 (s.e.) days. Fetal extracellular volume was expanded by infusion of 65 ±10-8 (s.e.) mL kg -1 estimated body weight of 0.15 M saline. This caused a decrease in fetal plasma protein concentrations (P < 0.01); fetal oncotic pressure decreased (P < 0.05). A diuresis and natriuresis occurred, which was due not to an increase in glomerular filtration rate but to a decrease in the fraction of the filtered sodium load reabsorbed by the proximal tubule (P < 0-05) and a decrease in the fraction of distally delivered sodium reabsorbed (P < 0.01). Fetal plasma protein concentrations were then increased to greater than control levels (P < 0.01) by infusion of maternal plasma (28±1-6mL kg -1 ); oncotic pressure was greater than after saline expansion (P < 0-05) and similar to control. The fraction of the filtered sodium load reabsorbed by the proximal tubule remained depressed (P < 0.01) relative to control, as did the fraction of distally delivered sodium that was reabsorbed (P < 0.01). Thus the natriuresis and diuresis continued. There was, however, a small effect of oncotic pressure on proximal fractional sodium reabsorption that was unmasked by multiple regression analysis. Obviously, this effect was not sufficient to override other effects of volume expansion on fetal proximal tubular function. Therefore, the reduction in fetal proximal fractional sodium reabsorption in volume expansion was not due solely to a fall in fetal oncotic pressure. Furthermore, since infusion of maternal plasma caused a rise in fetal plasma protein concentrations that was similar to the increase that would occur between 128 and 148 days gestation, it is unlikely that any gestation-dependent increase in proximal fractional sodium reabsorption is due solely to the increase in fetal plasma protein concentrations and hence oncotic pressure. © CSIRO 1995.

DOI 10.1071/RD9951321
Citations Scopus - 1
Co-authors E Lumbers
1995 Lumbers ER, 'Development of renal function in the fetus: A review', Reproduction, Fertility and Development, 7 415-426 (1995)

This review concentrated mainly on studies of intrauterine renal function carried out in chronically-catheterized fetal sheep. In sheep, as in primates, nephrogenesis is complete ... [more]

This review concentrated mainly on studies of intrauterine renal function carried out in chronically-catheterized fetal sheep. In sheep, as in primates, nephrogenesis is complete before birth. Studies in the rat and neonatal puppy provide insight into the functional development of the kidney, because these species are immature at birth and there is considerable postnatal renal development. Studies of the ovine fetus provide insight into the physiological role(s) of the kidneys during intrauterine life, albeit modified by changes related to maturation.

DOI 10.1071/RD9950415
Citations Scopus - 23
Co-authors E Lumbers
1995 Stevenson KM, Lumbers ER, 'Effects of angiotensin II in fetal sheep and modification of its actions by indomethacin.', The Journal of Physiology, 487 147-158 (1995)

1. Angiotensin II (AII) was infused I.V. into seven chronically catheterized fetal sheep (gestational age, 120-136 days). The effects of short-term infusions of 6 and 12 microgram... [more]

1. Angiotensin II (AII) was infused I.V. into seven chronically catheterized fetal sheep (gestational age, 120-136 days). The effects of short-term infusions of 6 and 12 micrograms kg-1 h-1 for 1.5 h were compared with the effects of infusing 6 micrograms kg-1 h-1 for 3 or 5 days (long-term infusion). AII produced an immediate rise in fetal arterial blood pressure (P < 0.025). When infused for 3 or 5 days, 6 micrograms kg-1 h-1 AII caused a greater increase in arterial blood pressure (P < 0.05). 2. Infusions of 6 micrograms kg-1 h-1 AII for 1.5 h had no effect on fetal placental blood flow or on flow to the fetal membranes, but after AII infusion for 3 or 5 days both flows were reduced (P < 0.01 and P < 0.005, respectively). Fetal blood gas status and pH were maintained. The only change in fetal renal function observed with short-term infusions of AII was a rise in sodium excretion when 12 micrograms kg-1 h-1 AII was given (P < 0.05). Infusion of 6 micrograms kg-1 h-1 for 3 or 5 days also caused a rise in sodium excretion (P < 0.025) because total and proximal fractional sodium reabsorptions were depressed (P < 0.01). Infusions of AII had no effects on the volume of lung liquid produced or on its composition. 3. Administration of indomethacin to the ewe (10 mg kg-1) and to the fetus (12 mg kg-1), during the infusion of AII, caused a rise in maternal arterial pressure (P < 0.01) but no change in fetal arterial pressure. 4. After indomethacin, umbilicoplacental blood flow rose (P < 0.05), as did fetal arterial PO2 (P < 0.05). Fetal arterial PCO2, pH and bicarbonate levels fell (P < 0.01). Glomerular filtration rate (GFR) rose (P < 0.01); there was a natriuresis (P < 0.01), chloriuresis (P < 0.01) and a kaliuresis (P < 0.05) but urine flow rate did not change. Lung liquid flow fell (P < 0.01). 5. It is concluded that in the fetus, long-term infusions of AII at a constant dose rate cause a progressive rise in arterial pressure. In addition, effects of AII on placental blood flow and on renal function develop. Thus, short-term infusions of AII cannot be used to predict the renal and cardiovascular effects of sustained high levels of this peptide in the fetus.(ABSTRACT TRUNCATED AT 400 WORDS) © 1995 The Physiological Society

DOI 10.1113/jphysiol.1995.sp020867
Citations Scopus - 18
Co-authors E Lumbers
1995 Stevenson KM, Gibson KJ, Lumbers ER, 'Comparison of the transplacental transfer of enalapril, captopril and losartan in sheep', British Journal of Pharmacology, 114 1495-1501 (1995)

1 The transplacental transfers of three drugs (enalapril, captopril and losartan) which block the renin angiotensin system and have different lipophilicities were studied in chron... [more]

1 The transplacental transfers of three drugs (enalapril, captopril and losartan) which block the renin angiotensin system and have different lipophilicities were studied in chronically catheterized foetal sheep (125¿139 days gestation). 2 The ability of the foeto-placental unit to convert enalapril to enalaprilat was studied in two chronically catheterized foetuses. Enalapril (3 mg kg -1 , 7.9 fimol kg -1 given i.v. to the foetuses abolished the foetal pressor response to 5 µg angiotensin I (AI) in one foetus and attenuated the pressor response in the other. 3 Enalapril (100 mg, 5.7 fimol kg -1 ) given i.v. to the ewe (n = 5) abolished the maternal pressor response to 2.5 µg AI (n = 1) and attenuated the maternal pressor response to 5 µg AI (n = 5, P < 0.001). The foetal pressor response to 5 µg AI (n = 2) and 10 µg AI (n = 3) did not change. The maternal and foetal pressor responses to angiotensin II (All; n = 5) did not change. 4 Foetal pressor responses to 5 µg AI (n = 1) and 10 µg AI (n = 2) were attenuated within 11 min of their mothers (n = 3) being given i.v. captopril (15 mg, 1.5 fimol kg-1). Foetal pressor responses to 5 µg All (n = 1) and to 10 µg All (n = 2) did not change. 5 Losartan (10 mg kg -1 , 21.7 fimol kg-1) given i.v. to the foetus (n = 9) attenuated the foetal pressor response to 5 µg All (P < 0.001) but the maternal pressor response to 5 µg All did not change. 6 Losartan (100 mg, 21.7 µmol kg-1) given i.v. to the ewe (n = 5) attenuated the maternal pressor response to 5 µg All (P < 0.002) but the foetal pressor response to 5 µg All did not change. 7 It is concluded that the foeto-placental unit of the sheep can metabolize enalapril to enalaprilat. Captopril readily crosses the sheep placenta but enalapril and losartan do not. Thus, the transplacental transfer of these drugs does not parallel their lipid solubilities. Furthermore the results show that AT 1 receptors are important in mediating the vasoconstrictor effects of All in the foetus. 1995 British Pharmacological Society

DOI 10.1111/j.1476-5381.1995.tb13376.x
Citations Scopus - 14
Co-authors E Lumbers
1995 Stevens AD, Lumbers ER, 'Effects of intravenous infusions of noradrenaline into the pregnant owe on uterine blood flow, fetal renal function, and lung liquid flow', Canadian Journal of Physiology and Pharmacology, 73 202-208 (1995)

To determine the effects on the fetus of high maternal levels of noradrenaline, experiments were carried out in 17 pregnant ewes (123-137 days gestation). Intravenous infusion of ... [more]

To determine the effects on the fetus of high maternal levels of noradrenaline, experiments were carried out in 17 pregnant ewes (123-137 days gestation). Intravenous infusion of 40 mg/min of norepinephrine to the ewe for 1.5 h increased maternal arterial pressure and significantly decreased maternal placental blood flow (p < 0.05). Fetal arterial pressure did not change, but fetal arterial PO 2 fell (p < 0.01) and PCO 2 , rose (p < 0.01). Fetal urine flow fell and osmolality rose (p < 0.01), fetal lung liquid flow and osmolar excretion fell (p < 0.01, p < 0.05, respectively), and the lung sodium:potassium ratio changed. These effects of high levels of maternal noradrenaline were transient, i.e., 2.5 h after the infusion of noradrenaline had finished, fetal urine flow and lung liquid flow had both returned to control values and fetal PCO 2 was significantly depressed relative to control values (p < 0.01). It is concluded that high levels of maternal catecholamines reduce placental blood flow and cause small changes in fetal oxygenation. These changes are sufficient to transiently affect fetal water excretion and to reduce lung liquid flow.

Citations Scopus - 15
Co-authors E Lumbers
1995 Gibson KJ, Lumbers ER, 'Extracellular volume and blood volume in chronically catheterized fetal sheep.', The Journal of Physiology, 485 835-844 (1995)

1. To determine the extracellular volume (ECV) in fetal sheep and its distribution between the plasma and interstitial spaces, ECV, blood volume (BV) and haematocrit were measured... [more]

1. To determine the extracellular volume (ECV) in fetal sheep and its distribution between the plasma and interstitial spaces, ECV, blood volume (BV) and haematocrit were measured in ten chronically catheterized fetal sheep aged 121-133 days. Relationships with age, weight and other fetal variables, including glomerular filtration rate (GFR), were studied. 2. ECV was measured as the mean of the volumes of distribution of [3H]inulin and [14C] mannitol extrapolated to time zero. The time zero volume of distribution was 1506 +/- 79 ml (means +/- S.E.M.) for inulin and 1590 +/- 80 ml for mannitol. The ECV was 1548 +/- 79 ml (632 +/- 18 ml (kg fetal wt)-1). BV, measured using 51Cr-labelled red cells, was 351 +/- 27 ml (141 +/- 6 ml kg-1). Haematocrit, plasma volume and interstitial volume were 34 +/- 1%, 229 +/- 17 ml (92 +/- 3 ml kg-1) and 1319 +/- 63 ml (540 +/- 17 ml kg-1), respectively. 3. Interstitial volume per kilogram fell with increasing fetal weight (P = 0.026). BV per kilogram did not change with weight or age. 4. The plasma: interstitial volume ratio was 0.17 +/- 0.01. This ratio increased as fetal weight and age increased (P = 0.026 and P = 0.044), that is, the proportion of ECV that was contained outside the vascular compartment was lower in heavier or older fetuses. 5. Since GFR was 3.4 +/- 0.4 ml min-1, the entire fetal ECV was filtered by the fetal kidney only 3.1 +/- 0.3 times per day. © 1995 The Physiological Society

DOI 10.1113/jphysiol.1995.sp020773
Citations Scopus - 15
Co-authors E Lumbers
1994 Lumbers ER, Menzies RI, Gibson KJ, Tyndale-Biscoe CH, 'Levels of active and inactive reninlike enzymes in plasma and reproductive tract of the pregnant wallaby', AM.J.PHYSIOL., 266 (1994)
Citations Scopus - 1
Co-authors E Lumbers
1994 Nail BS, Lumbers ER, Stevens AD, 'The effect of fetal lung inflation on fetal heart rate', American Journal of Physiology - Heart and Circulatory Physiology, 266 (1994)

The effect on the fetal heart by inflating the fetal lungs with liquid or air while the animal was being maintained in utero by its normal placental circulation was investigated i... [more]

The effect on the fetal heart by inflating the fetal lungs with liquid or air while the animal was being maintained in utero by its normal placental circulation was investigated in 10 healthy, chronically catheterized fetal sheep of gestational age 126-137 days. It was found that initial attempts to inflate the lungs with volumes of air as small as 10 ml (i.e., with less than a predicted normal tidal volume) caused abrupt, powerful slowing of the fetal heart with, usually, an associated hypotension. Inflations with similarly small volumes of saline were ineffective. Atropine pretreatment abolished the cardiac slowing caused by the air inflations, indicating the operation of a neural reflex. An analysis of the pressure changes induced by the air and liquid inflations in airway, intrathoracic and intra-amniotic pressures showed that the cardiac slowing was primarily related to the level of mechanical stress applied across the fetal airway.

Citations Scopus - 4
Co-authors E Lumbers
1994 Lumbers ER, Menzies RI, Gibson KJ, Tyndale-Biscoe CH, 'Levels of active and inactive reninlike enzymes in plasma and reproductive tract of the pregnant wallaby', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 266 (1994)

Active and total (acid-activated) levels of a reninlike enzyme (hereafter called renin) were measured in plasma, tissues, and yolk sac fluid of pregnant and postpartum wallabies. ... [more]

Active and total (acid-activated) levels of a reninlike enzyme (hereafter called renin) were measured in plasma, tissues, and yolk sac fluid of pregnant and postpartum wallabies. Plasma active renin generated angiotensin I (ANG I) from sheep angiotensinogen at 14 ± 1.3 (SE) ng · ml -1 · h - 1 , whereas acid-activated renin generated ANG I at 33.3 ± 2.5 ng · ml -1 · h -1 , i.e., 44.2 ± 3.7% of renin in plasma was active, and 58 ± 3.7% was inactive. Inactive renin levels were highest in pregnant animals (P = 0.05). Uterine renin was mainly inactive (95%); levels were 5.1 ± 1.1 times plasma levels. The levels of renin in nonpregnant uteri were the same as those in pregnant uteri from the same animals. Uterine renin levels did not change with gestation. Pooled acid-activated yolk sac fluid generated ANG I at low rates (0.7 and 1.6 ng · ml -1 · h -1 ); the acid-activated supernatant of a homogenate of pooled fetal membranes generated ANG I at 15 ng · g wet wt -1 · h - 1. Yolk sac fluid was strikingly different in electrolyte composition from maternal plasma. Its lower osmolality suggests that the membranes separating it from maternal plasma have a low permeability to water. Thus, although eutherian and marsupial mammals diverged 136-164 million years ago, the wallaby, like many eutherian mammals, has inactive renin in blood, in the female reproductive tract, and in fetal membranes.

Citations Scopus - 1
Co-authors E Lumbers
1994 Nail BS, Lumbers ER, Stevens AD, 'The effect of fetal lung inflation on fetal heart rate.', The American journal of physiology, 266 H1395-H1400 (1994)
Co-authors E Lumbers
1994 Lumbers ER, Menzies RI, Gibson KJ, Tyndale-Biscoe CH, 'Levels of active and inactive reninlike enzymes in plasma and reproductive tract of the pregnant wallaby.', The American journal of physiology, 266 R1353-R1358 (1994)
Co-authors E Lumbers
1994 Gibson KJ, Lumbers ER, 'Changes in renal function and blood volume in the newborn lamb delivered by cesarean section', Pediatric Research, 36 506-513 (1994)

To determine the cause of the transient natriuresis in lambs within 1-2 h of birth, renal function and blood volume (BV) were measured in nine chronically catheter-ized fetal shee... [more]

To determine the cause of the transient natriuresis in lambs within 1-2 h of birth, renal function and blood volume (BV) were measured in nine chronically catheter-ized fetal sheep aged 139-145 d before and after delivery by cesarean section. After delivery, sodium excretion increased 8-fold. This was due to a transient rise in glomerular filtration rate (by 39 ± 21%, p < 0.02) and a fall in fractional reabsorption of sodium by the proximal tubule from 63.4 ± 2.5% to 53.4 ± 3.4% (p < 0.01). The distal tubule failed to compensate fully for this fall, because fractional reabsorption by the distal tubule rose from 35.5 ± 2.4% to only 41.6 ± 2.2% (p < 0.05). The extent of the natriuresis did not depend on the lamb's initial BV per kg at birth. However, the amount of fluid excreted and the clearance of sodium during a 45-min period within the first 1-1.25 h after birth were approximately equal to the fall in BV that occurred during this time. Thus, most of the fall in BV that occurs after delivery is due to renal salt and water losses. Because the natriuresis was greater if the lamb's arterial pressure rose after birth, it is possible that a high arterial pressure in the immediate newborn period could result in salt and volume depletion. © 1994 International Pediatric Research Foundation, Inc.

Citations Scopus - 7
Co-authors E Lumbers
1993 Dawes J, Lumbers ER, 'Low molecular weight dermatan sulphate (Desmin 370) does not cross the ovine placenta', British Journal of Haematology, 84 90-94 (1993)

Summary. Transplacental passage of the low molecular weight dermatan sulphate Desmin 370 was investigated in pregnant sheep, using 125 I-labelled Desmin 370 to optimize the sens... [more]

Summary. Transplacental passage of the low molecular weight dermatan sulphate Desmin 370 was investigated in pregnant sheep, using 125 I-labelled Desmin 370 to optimize the sensitivity of the study. Chronically catheterized crossbred pregnant ewes at approximately 120 d gestation received 3700 kBq 125 I-labelled Desmin 370 with 1 mg/kg carrier unlabelled Desmin 370 intravenously. Early clearance from the maternal circulation was biexponential, and the volume of distribution corresponded closely with the theoretical value for distribution in total body water. Soon after injection low levels of radioactivity were detected in the fetal circulation and accumulated over the next 2 h, so that as the concentration of 125 I-Desmin 370 in the maternal circulation declined with time the fetal level of radiolabel rose to represent a significant concentration in relation to that in the mother. Radioactivity was also excreted into the fetal urine. However, while 50% of the radiolabeled material present in maternal plasma 150 min post-injection was intact Desmin 370 and the remaining 50% represented degradation products, fetal urine contained only these fragments. By contrast, intact Desmin 370 was readily excreted into fetal urine after direct introduction to the fetal circulation. Thus molecules of intact Desmin 370 with anticoagulant activity cannot cross the ovine placenta, and low molecular weight dermatan sulphates may be valuable for prophylaxis and treatment of thrombotic disease during pregnancy. Copyright © 1993, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1365-2141.1993.tb03029.x
Citations Scopus - 4
Co-authors E Lumbers
1993 Lumbers ER, Burrell JH, Menzies RI, Stevens AD, 'The effects of a converting enzyme inhibitor (Captopril) and angiotensin II on fetal renal function', British Journal of Pharmacology, 110 821-827 (1993)

Renal function was studied in chronically catheterized fetal sheep (119¿128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) i... [more]

Renal function was studied in chronically catheterized fetal sheep (119¿128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, Captopril, which crosses the placenta and blocks the fetal renin angiotensin system. An i.v. dose of 15 mg (about 319 µg kg -1 ) of Captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h -1 (about 128 µg kg -1 h -1 ) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 ± 5.6 to 84.9 ± 8.3 ml min -1 (mean ± s.e.mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01); fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). Ewes were treated for the next 2 days with 15 mg Captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of Captopril (6 mg h -1 ) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 µg kg -1 h -1 of angiotensin II was infused directly into the fetus RBF fell from 69 ± 10.1 ml min -1 to 31 ± 13.9 ml min -1 , GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses. It is concluded that the small fall in fetal arterial pressure partly contributed to the fall in fetal GFR but in addition, efferent arteriolar tone fell so that the filtration pressure fell further. Thus maintenance of fetal renal function depends on the integrity of the fetal renin angiotensin system. These findings explain why use of ACE inhibitors in human pregnancy is associated with neonatal anuria. 1993 British Pharmacological Society

DOI 10.1111/j.1476-5381.1993.tb13886.x
Citations Scopus - 59
Co-authors E Lumbers
1993 Gibson KJ, Lumbers ER, 'The roles of arginine vasopressin in fetal sodium balance and as a mediator of the effects of fetal 'stress'', Journal of Developmental Physiology, 19 125-136 (1993)

To see if arginine vasopressin (AVP) influenced fetal sodium balance, we infused AVP i.v. (45 mU h -1 kg -1 ) into two groups of chronically catheterized fetal sheep. One group h... [more]

To see if arginine vasopressin (AVP) influenced fetal sodium balance, we infused AVP i.v. (45 mU h -1 kg -1 ) into two groups of chronically catheterized fetal sheep. One group had urinary osmolalities of 147 ± 23 mosm kg -1 (SEM, n = 6) and the other group had higher urinary osmolalities (339 ± 3 mosm kg -1 , n = 4, P < 0.001). The group with high urinary osmolalities had higher systolic pressures (P < 0.05), higher glomerular filtration rates (GFR; P < 0.05), and higher urinary electrolyte excretion rates (P < 0.05), but lower membrane blood flows (P < 0.05) and lower fractional reabsorption of sodium by the proximal tubule (P < 0.01). In the group with low urinary osmolalities, AVP caused a rise in arterial blood pressure (P < 0.001), a fall in heart rate (P < 0.001), a fall in membrane blood flow (P < 0.02), but no change in placental or renal blood flow. Renal sodium excretion increased (P < 0.001) because GFR rose (P < 0.001) and proximal fractional sodium reabsorption fell (P < 0.001). Distal fractional sodium reabsorption increased (P < 0.001), but not enough to compensate for the fall in proximal fractional reabsorption. Lung liquid flow decreased (P = 0.006), as did lung liquid sodium excretion (P = 0.002). There were no changes in fetal plasma sodium, blood volume or haematocrit. The effects of AVP infusion were similar in the group with high urinary osmolalities. This study shows that high levels of AVP, such as occur in fetal 'stress', have widespread effects on fetal cardiovascular, renal and lung functions. The characteristic profile of the fetuses with high urinary osmolalities prior to AVP infusion could be entirely explained by high endogenous AVP levels and AVP could possibly be a sole mediator of these widespread effects of fetal 'stress'. Furthermore, although during infusion of AVP sodium excretion increased, blood volumes did not change. Therefore, the fetuses must have accessed additional sodium from either their extracellular fluids, the amniotic and/or allantoic cavities or across the placenta.

Citations Scopus - 21
Co-authors E Lumbers
1992 Lumbers ER, Kingsford NM, Menzies RI, Stevens AD, 'Acute effects of captopril, an angiotensin-converting enzyme inhibitor, on the pregnant ewe and fetus', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 262 (1992)

After control measurements had been made, 15 chronically catheterized pregnant ewes (gestational age 123-141 days) were given 15 mg of captopril intravenously followed by an infus... [more]

After control measurements had been made, 15 chronically catheterized pregnant ewes (gestational age 123-141 days) were given 15 mg of captopril intravenously followed by an infusion of 6 mg/h. These doses blocked the pressor responses of both ewes and fetuses to 5 µg of angiotensin I. After captopril, maternal mean arterial pressure fell from 94 ± 3.5 to 88 ± 3.6 (SE) mmHg (P < 0.0001) and pulse interval fell (P = 0.008). Maternal flow to the cotyledons fell from 766 ± 118 to 525 ± 77 ml/min (P = 0.002), as did flow to the remainder of the maternal placenta, i.e., the caruncles and their underlying myoendometrium (control flow 188 ± 35 ml/min, flow 10-15 min after captopril 166 ± 36.1 ml/min; P = 0.021). Flow to the rest of the myometrium did not change. Fetal arterial pressure fell from 46.9 ± 1.6 to 44.1 ± 1.6 mmHg (P < 0.009), and fetal placental blood flow fell from 639.9 ± 93.2 to 413.1 ± 53.9 ml/min (P = 0.025). Flow to the fetal membranes declined also, from 53.2 ± 6.5 to 35.6 ± 3.3 ml/min (P < 0.005). Maternal and fetal renal blood flows and fetal adrenal blood flows were unchanged. Fetal arterial PO 2 was initially 19.5 ± 0.8 mmHg; after captopril, it was 17.7 ± 0.9 mmHg (P = 0.03). Fetal urine flow rate fell from 0.66 ± 0.08 ml/min to a nadir of 0.25 ± 0.08 ml/min (P < 0.0001) while urinary osmolality rose from 108 ± 5 mosmol/kgH 2 O to a maximum of 229 ± 42 mosmol/kgH 2 O at the end of the experiment (P = 0.001). Sodium excretion (P = 0.022) also declined from 15.8 ± 2.6 to 8.8 ± 1.7 µmol/min. It is concluded that captopril induces maternal hypotension and falls in maternal and fetal placental flows, which leads to changes in fetal blood gases and fetal renal function. However, there may also be direct effects of captopril on fetal renal function.

Citations Scopus - 35
Co-authors E Lumbers
1992 Lumbers ER, Kingsford NM, Menzies RI, Stevens AD, 'Acute effects of captopril, an angiotensin-converting enzyme inhibitor, on the pregnant ewe and fetus.', The American journal of physiology, 262 R754-R760 (1992)
Co-authors E Lumbers
1992 Gibson KJ, Lumbers ER, 'Mechanisms by which the pregnant ewe can sustain increased salt and water supply to the fetus.', The Journal of Physiology, 445 569-579 (1992)

1. Nine chronically catheterized pregnant ewes were monitored before, during and after 1 week in which fetal urine was drained continuously, to determine whether they could compen... [more]

1. Nine chronically catheterized pregnant ewes were monitored before, during and after 1 week in which fetal urine was drained continuously, to determine whether they could compensate for the resulting loss of salt and water and increase net supply across the placenta to the fetus. 2. Fetal growth and urine and lung liquid production were not affected by loss of all fetal fluids. 3. When fetal urine was drained, the increase (P less than 0.05) in maternal drinking was greater than the extra amount of fluid lost. Thus, maternal plasma osmolality fell (P less than 0.01). When fetal urine again flowed into the amniotic and allantoic cavities, maternal drinking did not fall significantly and plasma osmolality remained low. Maternal urine flow rate increased (P less than 0.05) and its osmolality fell (P less than 0.02). 4. Maternal food intake increased (P less than 0.005) during fetal urine drainage. 5. Maternal plasma renin activity increased (P less than 0.05), her urinary sodium excretion fell (P less than 0.005) and the Na(+)-K+ ratio in both her urine and faeces decreased (P less than 0.01 and P less than 0.05 respectively) when fetal urine was drained. Maternal urinary and faecal sodium conservation continued after drainage ceased because of continued loss of sodium in lung liquid. 6. It is concluded that the ewe can compensate for inappropriate loss of salt and water from the conceptus. © 1992 The Physiological Society

DOI 10.1113/jphysiol.1992.sp018940
Citations Scopus - 18
Co-authors E Lumbers
1992 Moore RS, Lumbers ER, 'Renal and metabolic effects of glucagon in the fetus', Journal of Developmental Physiology, 17 47-49 (1992)

The effects of pharmacological doses of glucagon (0.5 µg/kg/min) were studied in 8 chronically-catheterised fetal sheep. These doses of glucagon raised fetal blood glucose. and c... [more]

The effects of pharmacological doses of glucagon (0.5 µg/kg/min) were studied in 8 chronically-catheterised fetal sheep. These doses of glucagon raised fetal blood glucose. and caused a small fall in fetal arterial PO 2 (P < 0.05). Arterial PCO 2 rose (P < 0.05) and pH fell (P < 0.05) while plasma osmolality increased (P < 0.01). There were no effects of glucagon on fetal renal function but in the fetus, like the adult, i.v. glucagon caused increases in heart rate (P < 0.01) which were not associated with changes in arterial pressure.

Citations Scopus - 3
Co-authors E Lumbers
1992 Stevenson KM, Lumbers ER, 'Effects of indomethacin on fetal renal function, renal and umbilicoplacental blood flow and lung liquid production', Journal of Developmental Physiology, 17 257-264 (1992)

The effects of indomethacin (10 mg/kg i.v. to the ewe and 12 mg/kg i.v. to the fetus) were examined in 8 chronically catheterized fetal sheep (117-138 days gestation). These doses... [more]

The effects of indomethacin (10 mg/kg i.v. to the ewe and 12 mg/kg i.v. to the fetus) were examined in 8 chronically catheterized fetal sheep (117-138 days gestation). These doses suppressed fetal 6-keto-prostaglandin F(1a) and thromboxane B 2 levels. Fetal arterial PO 2 increased (P < 0.01); PCO 2 (P < 0.001) and pH fell (P < 0.001) and arterial pressure did not change. Placental blood flow increased in 4 of the 5 fetuses in which blood flows were measured. Lung liquid flow rate fell (P < 0.001). Fetal renal blood flow did not change but its distribution did, i.e. flow to the inner part of the renal cortex decreased (P < 0.05). Urine flow rates did not change but there was a natriuresis (P < 0.02), kaliuresis (P < 0.02) and chloriuresis (P < 0.02). Urinary osmolality rose (P < 0.001) and free water clearance fell (P=0.004). It is concluded that when indomethacin is administered to both ewe and fetus, the resulting fall in prostaglandin I 2 and thromboxane A 2 levels causes marked changes in fetal blood gas status, renal function and lung liquid production. These effects are more profound than those seen when indomethacin is given only to the fetus. They do not however, explain the reason why clinical use of indomethacin is associated with a reversible oligohydramnios.

Citations Scopus - 20
Co-authors E Lumbers
1992 Tangalakis K, Lumbers E, Moritz K, Towstoless M, Wintour E, 'Effect of cortisol on blood pressure and vascular reactivity in the ovine fetus', Experimental Physiology, 77 709-717 (1992)

The aim of this study was to investigate the cardiovascular effects of exogenous cortisol in fetal sheep, (a) between 100 and 120 days of gestation when cortisol production is min... [more]

The aim of this study was to investigate the cardiovascular effects of exogenous cortisol in fetal sheep, (a) between 100 and 120 days of gestation when cortisol production is minimal and (b) after 130 days when endogenous plasma cortisol starts to rise. Chronically cannulated ovine fetuses (103¿120 days, n = 9; 130¿137 days, n = 7), received sequentially a 24 h infusion of vehicle (0.9% sodium chloride) and a 24 h infusion of cortisol at 100 micrograms/h. Blood pressure and heart rate changes to bolus injections each of angiotensin II and noradrenaline (0.2, 0.5, 1.0, 2.0 micrograms) were measured before and after the saline and cortisol infusions. Fetuses in each age group, served as additional controls receiving 48 h saline infusions. In both immature and mature age groups, the cortisol infusion increased basal fetal blood cortisol concentrations by 33.7 and 35.4 nmol/l respectively. In the immature group, cortisol, but not saline, caused significant 14.3 and 15.3% increases in basal systolic and diastolic pressures respectively. Basal blood pressure was higher in the mature group, but did not increase further despite the increase in cortisol levels. Furthermore, vascular responsiveness to angiotensin II but not to noradrenaline was significantly enhanced following the cortisol infusion, at both ages. Fetal heart rate did not change following the cortisol infusion. Exogenous cortisol contributes to the regulation of fetal blood pressure in the immature fetus, when other mechanisms have not developed. Cortisol might achieve this, in part, by enhancing vascular sensitivity to angiotensin II. © 1992 The Physiological Society

DOI 10.1113/expphysiol.1992.sp003637
Citations Scopus - 146
Co-authors E Lumbers
1991 Lumbers ER, Moore RS, Stevens AD, Gibson KJ, 'Changes in fetal and maternal plasma protein concentration and colloid osmotic pressure with gestation', Journal of Developmental Physiology, 15 347-350 (1991)

In pregnant ewes, plasma protein levels over the gestation age range of 58-141 days fell progressively (r=-0.332, P < 0.05, n=36) but colloid osmotic pressure (COP, mmHg) did not ... [more]

In pregnant ewes, plasma protein levels over the gestation age range of 58-141 days fell progressively (r=-0.332, P < 0.05, n=36) but colloid osmotic pressure (COP, mmHg) did not change significantly. In fetal sheep carried by these ewes, plasma protein levels increased with age (r=0.85, P < 0.00001, n=32) . COP also rose (r=0.8, P < 0.00001, n=23). Since maternal COP did not change and fetal COP increased, the net transplacental COP gradient between mother and fetus decreased with increasing age (r=-0.589, P < 0.004, n=22). Fetal plasma protein levels can be used to calculate fetal COP while maternal plasma protein levels cannot be used to calculate maternal COP.

Citations Scopus - 4
Co-authors E Lumbers
1991 Lumbers ER, Kingsford NM, Menzies RI, 'The relationships between fetal and maternal placental blood flows', Journal of Developmental Physiology, 16 125-132 (1991)

Individual maternal and fetal flows to 706 placental cotyledons obtained from 9 chronically catheterized pregnant ewes and their fetuses (gestation age 123 - 141 days) were measur... [more]

Individual maternal and fetal flows to 706 placental cotyledons obtained from 9 chronically catheterized pregnant ewes and their fetuses (gestation age 123 - 141 days) were measured. The larger the cotyledon the greater the maternal and fetal blood flow to it. Both fetal and maternal flows to larger cotyledons, however, tended to be lower when corrected for the weight of the cotyledon perfused. Changes in fetal placental flow (dfg(c) = ml/min/g) occurring within 15 min of administration of 15 mg i.v. of captopril to the ewe were dependent on changes in fetal placental vascular resistance (dcot(f)r) and maternal flow (dmg(c)) according to the equation dfg(c) = 0.123 + 0.185 dmg(c) - 0.026 dcot(f)r. Changes in maternal placental flow occurring within 15 min of administration of 15 mg i.v. of captopril to the ewe were dependent on changes in maternal placental vascular resistance (dcot(m)r) and changes in fetal flow according to the equation dmg(c) = 0.483 + 0.496 dfg(c) - 0.0198 dcot(m)r. The changes in fetal flow over the next 1.5 h of treatment with captopril at 6 mg/h were dependent on neither changes in fetal placental vascular resistance nor maternal placental flow. Changes in maternal placental flows over the same time were no longer related to changes in fetal flow and depended only to a minimal extent on changes in maternal placental resistance. These analyses suggest that treatment of the pregnant ewe with captopril may have disturbed the normal relationships between maternal and fetal placental circulations.

Citations Scopus - 5
Co-authors E Lumbers
1990 Stevens AD, Lumbers ER, 'Effects of reduced uterine blood flow on fetal cardiovascular, renal, and lung function', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 259 (1990)

Uterine blood flow (UBF) was reduced for 1 h by partially occluding the maternal aorta below the renal arteries in seven pregnant ewes (gestation age 126-134 days). Fetuses became... [more]

Uterine blood flow (UBF) was reduced for 1 h by partially occluding the maternal aorta below the renal arteries in seven pregnant ewes (gestation age 126-134 days). Fetuses became hypoxic, acidemic, and hypercapnic. They developed hypertension (P < 0.005) and a bradycardia (P < 0.05). During restricted UBF, fetal hematocrit (Hct) rose (P < 0.005) and blood volume fell in five of seven fetuses. After release of constriction, fetal Hct fell, and blood volume rose by 7.5 ± 3.26% (P < 0.05) relative to control. During reduced UBF, lung liquid and urine flow rates fell (P < 0.025 and P < 0.05, respectively). After the occluder was released, Na excretion (which did not fall significantly during reduced UBF) increased (P < 0.05), and fractional reabsorption of Na fell (P < 0.05). Changes in fetal blood volume (FBV) were directly related to changes in maternal lower body flow (r = 0.47, P = 0.01, n = 33), and changes in fetal Hct were inversely related to maternal flow (r = -0.635, P = 0.001). Fetal urinary Na excretion per kilogram body weight was directly related to FBV per kilogram (r = 0.44, P = 0.005, n = 40), whereas fractional reabsorption of Na was inversely related to FBV per kilogram body wt (r = 0.48, P < 0.002, n = 39). It is concluded that reductions in UBF cause fetal hypoxemia and acidemia, which lead to changes in fetal cardiovascular function and in FBV. These changes lead to marked changes in fetal renal function and lung liquid flow and could account for the variability in urinary osmolality and Na excretion often seen in chronically catheterized fetal sheep.

Citations Scopus - 12
Co-authors E Lumbers
1990 Stevens AD, Lumbers ER, 'Effects of reduced uterine blood flow on fetal cardiovascular, renal, and lung function.', The American journal of physiology, 259 R1004-R1011 (1990)
Co-authors E Lumbers
1990 Leader LR, Smith FG, Lumbers ER, 'The effect of ethanol on habituation and the cardiovascular response to stimulation in fetal sheep', European Journal of Obstetrics and Gynecology and Reproductive Biology, 36 87-95 (1990)

Fetal cardiovascular (CVS) changes, forelimb movements (FM) and rates of habituation to repeated stimulation, with suffusions of cold saline over the skin, were measured in 12 chr... [more]

Fetal cardiovascular (CVS) changes, forelimb movements (FM) and rates of habituation to repeated stimulation, with suffusions of cold saline over the skin, were measured in 12 chronically catheterized fetal sheep aged 130-145 days. Stimulation of the fetuses caused a significant rise in heart rate (HR) (p < 0.01) and blood pressure (BP) (p < 0.001) and FM (p < 0.01). When the ewe was given an intravenous (i.v.) infusion of ethanol which produced fetal ethanol levels of 87 ± 1.1 mg/100 ml, the number of spontaneous FM decreased (p < 0.05). After i.v. ethanol, repeated stimulation of the fetuses still caused an increase in FM (p < 0.01) and a rise in HR (p < 0.05) and BP (p < 0.02) but the fetuses habituated more rapidly (7.25 ± 1.28 stimuli) compared to control experiments performed prior to (21.5 ± 3.57 stimuli) or after the ethanol (17.75 ± 5.83, p < 0.01). Fetal exposure to low concentrations of ethanol does affect the patterns of response and habituation of the developing fetal central nervous system. © 1990.

DOI 10.1016/0028-2243(90)90054-5
Citations Scopus - 4
Co-authors E Lumbers
1990 Kairaitis K, Lumbers ER, 'The influence of endogenous mineralocorticoids on the composition of fetal urine', Journal of Developmental Physiology, 13 347-351 (1990)

Experiments were carried out in 10 chronically catheterised fetal sheep aged 121-128 days. In 3 animals infusion of aldosterone (5 µg/h) caused a fall in fetal urinary Na/K ratio... [more]

Experiments were carried out in 10 chronically catheterised fetal sheep aged 121-128 days. In 3 animals infusion of aldosterone (5 µg/h) caused a fall in fetal urinary Na/K ratio; an effect that was reversed by spironolactone 2.5 mg/kg followed by an infusion of 100 µg/h per kg. In 9 fetal sheep which had no previous treatment the same dose of spironolactone had no effect on fractional sodium excretion although the fractional excretion of potassium decreased (P < 0.05) and the urinary sodium potassium (Na/K) ratio rose (P < 0.05). Amiloride had a variable effect on sodium excretion but the fractional excretion of potassium decreased markedly (P < 0.05). Thus in chronically catheterised fetal sheep, endogenous mineralocorticoid activity altered urinary potassium excretion and the urinary Na/K ratio. However, this activity was low, as distal blockade with amiloride further decreased the fractional excretion of potassium and increased the urinary Na/K ratio.

Citations Scopus - 11
Co-authors E Lumbers
1990 Lumbers ER, 'EFFECTS ON SHEEP BLOOD PRESSURE OF TREATMENT WITH ANGIOTENSIN, STEROIDS AND SALT', Clinical and Experimental Pharmacology and Physiology, 17 315-319 (1990)

1. Angiotensin II (AII, 0.22 µg/min) infused for 7¿14 days, into adult unanaesthetized wethers, caused a rise in blood pressure of 7±3/7±3 mmHg (mean ± s.e.m.) from control v... [more]

1. Angiotensin II (AII, 0.22 µg/min) infused for 7¿14 days, into adult unanaesthetized wethers, caused a rise in blood pressure of 7±3/7±3 mmHg (mean ± s.e.m.) from control values of 90±5/54±3 mmHg (P < 0.05, n= 11). Cardiac output and pulse interval were not affected. A high salt intake had no effect on blood pressure, cardiac output and pulse interval, nor did it potentiate the action of AII. 2. Ethinyl oestradiol (EE, 20 mg/week) caused a small fall in systolic and diastolic pressure of 6±3/6±5 mmHg (n= 7, P < 0.1, P < 0.05). When AII (0.22 µg/min) was given with EE, it still caused a significant rise in blood pressure (P < 0.01). The synthetic progestin (1 mg of norethisterone [NE] for 8¿18 days) plus a high salt diet had no effect on arterial pressure and cardiac output but pulse interval rose significantly (P < 0.05). 3. Therefore the reduction in vascular reactivity to angiotensin seen in human pregnancy is probably not related to high levels of oestrogen. Further, NE combined with a high salt diet does not cause hypertension in sheep. Copyright © 1990, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1440-1681.1990.tb01327.x
Co-authors E Lumbers
1990 Elbourne I, Lumbers E, Hill K, 'The secretion of organic acids and bases by the ovine fetal kidney', Experimental Physiology, 75 211-221 (1990)

Excretion of organic acids and bases was studied in twelve fetal sheep aged 120-140 days. There was no significant plasma protein binding of the organic anion, p-aminohippurate (P... [more]

Excretion of organic acids and bases was studied in twelve fetal sheep aged 120-140 days. There was no significant plasma protein binding of the organic anion, p-aminohippurate (PAH), nor of the organic cation, [14C]tetraethylammonium (TEA). There was a significant amount of acetyl-PAH (20 +/- 3%) in fetal urine but none could be detected in fetal plasma. The fractional excretion of unconjugated PAH was less than one, i.e. there was net reabsorption of 31.7 +/- 3.9% of the filtered load of unconjugated PAH. Since there was no acetyl-PAH in fetal plasma it is concluded that all acetyl-PAH in fetal urine occurred as a result of metabolism of PAH and secretion of the metabolite into the tubular lumen. The rate of excretion of acetyl-PAH in fetal urine varied from 0 to 14.0 micrograms min-1. Thus unconjugated PAH is filtered and there is net reabsorption; in addition, PAH is metabolized and enters the urine via tubular mechanisms. The fractional excretion of PAH was unaffected by I.V. administration of penicillin either acutely or chronically. The clearance of [14C] TEA was significantly greater than the glomerular filtration rate (GFR). The mean fractional excretion of [14C]TEA was 5.4 +/- 0.17. Thus 80.7 +/- 0.63% of the excreted TEA was secreted. The clearance of TEA was related to body weight (P less than 0.001) but the fractional excretion of TEA declined with gestation age, probably because GFR increased at a greater rate than the rate at which the secretory pathways increase their activity. It is concluded that those pathways that excrete organic anions like PAH into the urine mature much later (probably after birth) than those pathways responsible for the tubular secretion of organic bases. © 1990 The Physiological Society

DOI 10.1113/expphysiol.1990.sp003395
Citations Scopus - 23
Co-authors E Lumbers
1989 Leader LR, Smith FG, Lumbers ER, Stevens AD, 'Effect of hypoxia and catecholamines on the habituation rates of chronically catheterized ovine fetuses', Biology of the Neonate, 56 218-227 (1989)

Integrated electromyographic, electrocortical (ECoG) and electro-ocular activity were recorded in 13 chronically prepared fetal sheep (130-145 days). Fetal movements and the rate ... [more]

Integrated electromyographic, electrocortical (ECoG) and electro-ocular activity were recorded in 13 chronically prepared fetal sheep (130-145 days). Fetal movements and the rate of habituation to repeated suffusions of cold saline agains the fetal skin were recorded. Experiments were repeated during an intravenous infusion of noradrenaline to the fetus (0.4 µg/kg estimated fetal weight/min) and during hypoxia induced by altering the oxygen content of the inspired air to the ewe to 9%. Repeated stimulation with cold saline resulted in an increase in fetal movements (p = 0.009). The number of stimuli for habituation was similar in high-voltage and in low-voltage ECoG activity. The rate of fetal habituation was significantly faster during the infusion of noradrenaline compared with control measurements (p = 0.009). During hypoxia, the number of spontaneous fetal movements prior to stimulation decreased (p = 0.002). Habituation rates were also faster during hypoxemia compared with control measurements (p = 0.003). These findings may help to explain the rapid habituation rates seen in some human fetuses in at 'at risk' pregnancies.

Citations Scopus - 5
Co-authors E Lumbers
1989 Smith FG, Lumbers ER, 'Comparison of renal function in term fetal sheep and newborn lambs', Neonatology, 55 309-316 (1989)

Renal function was measured in fetal sheep, in neonates following delivery by caesarean section, and in lambs in the first week of life. The most marked changes in renal function ... [more]

Renal function was measured in fetal sheep, in neonates following delivery by caesarean section, and in lambs in the first week of life. The most marked changes in renal function following delivery were an increase in glomerular filtration rate from 4.59 ± 0.27 ml/min (n = 13) to 6.94 ± 1.00 ml/min (n = 12), a decrease in urine flow, sodium and osmolar excretion rates and an increase in urinary osmolality. Fractional sodium reabsorp-tion increased from 95.5 ± 0.79% (n = 13) in the fetus to 99.4 ± 0.14% (n = 12, p < 0.001) in lambs aged 24 h or more; fractional osmolar reabsorption rose from fetal levels of 92.3 ±0.84% (n = 13) to 96.5 ± 0.52% (n = 11; p < 0.001) in lambs aged 24h or more. Potassium excretion and fractional potassium reabsorption did not alter after birth. Urinary osmolality increased from 175 ± 20.4 mosm/kg H2O (n = 14) to 524 ± 45.6 mosm/kg H2O (n = 16; p < 0.001) in lambs aged 24 h or more, and free water clearance decreased from 0.308 ± 0.06 ml/min (n = 13)to-0.067 ± 0.03 ml/min (n = 15; p < 0.001). Since the above changes occurred within 24 h of delivery, they represent rapid adjustments by the kidney to lack of a placental supply of fluid and electrolytes. © 1989 S. Karger AG, Basel.

DOI 10.1159/000242933
Citations Scopus - 11
Co-authors E Lumbers
1989 Kingsford NM, Lumbers ER, 'EFFECTS OF AUTONOMIC BLOCKADE ON THE HYPERTENSIVE RESPONSE OF THE FETUS TO HYPEROSMOLALITY', Clinical and Experimental Pharmacology and Physiology, 16 873-883 (1989)

1. Infusions of hyperosmotic mannitol to the ewe caused a rise in fetal arterial pressure in 17 chronically catheterized fetal sheep aged 120¿140 days. The fetal heart slowed in ... [more]

1. Infusions of hyperosmotic mannitol to the ewe caused a rise in fetal arterial pressure in 17 chronically catheterized fetal sheep aged 120¿140 days. The fetal heart slowed in 13 out of 17 of these fetuses. The rise in pressure occurred before there was any rise in fetal urinary osmolality. 2. In seven fetal sheep combined a- and ß-adrenoceptor and muscarinic blockade delayed the onset of the rise in blood pressure and no bradycardia was observed. It is concluded that the hypertension was due in part to increased activity of the sympatho-adrenal system, and that any reflex bradycardia that occurred was mediated by the vagus. 3. In three other fetal sheep aged 125¿131 days, the cardiovascular responses elicited by infusion of hyperosmotic mannitol to the ewe were not blocked by a specific vasopressin antagonist. Thus vasopressin could not be responsible for either the initial rise in pressure nor the delayed hypertensive response that was not blocked by a- and ß-adrenoceptor blockade. 4. Fetal blood volume was maintained even though the changes in plasma osmolality and electrolytes were indicative of a fall in blood volume. Thus changes that threaten maintenance of fetal blood volume seem to induce increased solute and water transport across the placenta or from the extracorporeal fluid compartments. Copyright © 1989, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1440-1681.1989.tb01527.x
Citations Scopus - 3
Co-authors E Lumbers
1989 Lumbers ER, Smith FG, 'MEASUREMENT OF NET SODIUM INTAKE BY THE OVINE FETUS WITH OESOPHAGEAL LIGATION', Clinical and Experimental Pharmacology and Physiology, 16 859-866 (1989)

1. If the fetal sheep is in sodium balance, then the net intake of sodium is equal to the sum of the losses of sodium in fetal urine and lung liquid plus the rate of deposition of... [more]

1. If the fetal sheep is in sodium balance, then the net intake of sodium is equal to the sum of the losses of sodium in fetal urine and lung liquid plus the rate of deposition of sodium with growth. 2. In seven fetal sheep with oesophageal ligation net sodium intake was 23.1 ± 2.8 (s.e.m.) µmol/min per kg; 11.8 ± 1,4 µmol/min per kg was excreted by the lungs and 8.7 ± 2.3 µmol/min per kg was excreted by the kidneys. The excretion of sodium by the lungs accounted for 52.8 ± 4.8% of the total amount of sodium; the excretion of sodium by the kidneys accounted for 34.9 ± 5.4% and the calculated variable, that is, sodium deposited due to growth was 12.3 ± 1.4%. 3. All but one fetus excreted more sodium from the lungs than from the kidneys. There was no relationship between the clearance of sodium by the lungs and net sodium intake but there was a direct relationship between renal sodium clearance and net sodium intake (r=0.92, P < 0.005). This suggests that fetal urinary sodium excretion is dependent upon net sodium intake by the fetus. This animal model shows that normally there must be sodium fluxes from allantoic and/or amniotic cavities to either the fetus or the ewe. Copyright © 1989, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1440-1681.1989.tb01525.x
Citations Scopus - 5
Co-authors E Lumbers
1988 Smith FG, Lumbers ER, 'Effects of maternal hyperglycemia on fetal renal function in sheep', American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 255 (1988)

The effects of maternal hyperglycemia on fetal renal function were investigated in 10 chronically catheterized fetal sheep after the infusion of 100 g of glucose into the ewe over... [more]

The effects of maternal hyperglycemia on fetal renal function were investigated in 10 chronically catheterized fetal sheep after the infusion of 100 g of glucose into the ewe over 30 min. Fetal blood glucose levels rose (P < 0.001) within 15 min of completing the glucose infusion from 15.75 ± 2.8 to 195.4 ± 18 (SE) mg/dl (n = 10). There was a significant increase in fetal glomerular filtration rate (P < 0.005) from 2.73 ± 0.41 to 3.65 ± 0.40 (SE) ml/min (n = 10) within 1.5 h of the infusion of glucose into the ewe. Urine flow rate increased from 0.38 ± 0.06 to 0.63 ± 0.12 (SE) ml/min (n = 10, P < 0.001), and sodium excretion increased from 18.42 ± 7.21 to 38.4 ± 13.7 (SE) µmol/min (n = 10, P < 0.002) within 2.5 h of the infusion of glucose into the ewe. The fraction of the filtered load that was excreted (urine flow rate divided by glomerular filtration rate) also increased (P < 0.01) as did the fraction of the osmolar load (P < 0.002). Glycosuria occurred in all fetuses within 30 min of the infusion of glucose into the ewe, and glucose excretion reached 26.16 ± 12.36 (SE) µg/min (n = 8) after 1.5 h. These findings of diuresis, natriuresis, and glycosuria in response to hyperglycemia are evidence that an increased delivery of fluid into the amniotic cavity might occur after a rise in fetal plasma glucose levels.

Citations Scopus - 12
Co-authors E Lumbers
1988 Smith FG, Lumbers ER, 'Effects of maternal hyperglycemia on fetal renal function in sheep.', The American journal of physiology, 255 F11-F14 (1988)
Co-authors E Lumbers
1988 Leader LR, Stevens AD, Lumbers ER, 'Measurement of fetal responses to vibroacoustic stimuli. Habituation in fetal sheep', Biology of the Neonate, 53 73-85 (1988)

Electrocortical (ECoG) and integrated electromyographic (EMG) activity was recorded in 6 chronically prepared fetal sheep (132-145 days). Recordings were made in fetuses prior to ... [more]

Electrocortical (ECoG) and integrated electromyographic (EMG) activity was recorded in 6 chronically prepared fetal sheep (132-145 days). Recordings were made in fetuses prior to and during repeated vibroacoustic stimulation. In the undisturbed fetus, two patterns of ECoG activity were apparent; high (HV) and low voltage (LV). The fetus responded to this broad spectrum stimulus during both LV and HV ECoG activity. In 18 of the 20 experiments, repeated stimulation was not associated with a change in the background ECoG activity. All fetuses responded at least once to the stimulus. Habituation of the EMG response was observed during both HV and LV ECoG activity. The rate of habituation was independent of the background ECoG activity and was unchanged when experiments were repeated at intervals of more than 3 days. These results show that fetal sheep also respond to vibroacoustic stimulation and with repetition habituation occurs.

Citations Scopus - 25
Co-authors E Lumbers
1988 Lumbers ER, Hill KJ, Bennett VJ, 'Proximal and distal tubular activity in chronically catheterized fetal sheep compared with the adult', Canadian Journal of Physiology and Pharmacology, 66 697-702 (1988)

Renal function was studied in unanaesthetized fetal sheep aged 112-120 and 126-132 days and in adult nonpregnant ewes. The clearance of lithium was used to measure proximal and di... [more]

Renal function was studied in unanaesthetized fetal sheep aged 112-120 and 126-132 days and in adult nonpregnant ewes. The clearance of lithium was used to measure proximal and distal fractional sodium reabsorption. In five nonpregnant adult sheep, 80.6 ± 1.7% (SE) of the filtered sodium load was reabsorbed proximally and 18.2 ± 1.53% distally. This was different from all groups of fetal sheep (p < 0.001). In younger fetuses, proximal fractional sodium reabsorption was less (51.3 ± 2.3% (SE), p < 0.05 and distal fractional sodium reabsorption greater (42.4 ± 2.3% (SE), p < 0.05) than older fetuses (126-132 days old) in which 61.4 ± 2.4% (SE) was reabsorbed proximally and 33.6 ± 2.5% (SE) distally. In another group of fetuses aged 125-137 days, in which proximal tubular sodium reabsorption was measured after distal tubular blockade, proximal fractional sodium reabsorption was 57.8 ± 2.95 (SE) and distal fractional sodium reabsorption, 38.7 ± 2.64% (SE). In adult sheep there was no relationship between distal tubular sodium reabsorption and glomerular filtration rate, i.e., proximal tubular function was responsible for glomerulotubular balance. However, in the fetuses, both proximal and distal tubular sodium reabsorption contributed to glomerulotubular balance. Thus in fetal life, the proximal tubule participates to a lesser extent in reabsorbing the filtered sodium load possibly because its function is suppressed by its relatively 'volume-expanded' state or because it is functionally immature. Therefore, a greater proportion is reabsorbed distally and the distal nephron participates under physiological conditions in glomerulotubular balance.

Citations Scopus - 51
Co-authors E Lumbers
1988 Kesby GJ, Lumbers ER, 'The effects of metabolic acidosis on renal function of fetal sheep.', The Journal of Physiology, 396 65-74 (1988)

1. The effects of I.V. infusions of 6.7-19.3 mmol hydrochloric acid/kg on fetal renal function were studied in fourteen chronically catheterized fetal sheep aged 121-143 days. Inf... [more]

1. The effects of I.V. infusions of 6.7-19.3 mmol hydrochloric acid/kg on fetal renal function were studied in fourteen chronically catheterized fetal sheep aged 121-143 days. Infusion of acid caused arterial pH and plasma bicarbonate levels to fall (P less than 0.0005, P less than 0.001). These remained low for the next 3 h. Plasma chloride levels increased (P less than 0.0005). There were no other changes in plasma electrolytes nor in plasma osmolality. 2. Fetal glomerular filtration rate did not change; the fractional reabsorptions of sodium, chloride and phosphate all decreased (P less than 0.005). Initially urine volume did not change but urinary osmolality increased (P less than 0.0005). Fetal urinary pH fell abruptly, titratable acid excretion increased, urinary ammonium excretion increased (P less than 0.0005) but urinary bicarbonate excretion remained unchanged. Thus, net acid excretion increased significantly (P less than 0.0005). 3. Twenty-six hours after infusion of acid, fetal arterial pH, bicarbonate levels, urinary pH, titratable acid and ammonium excretion were no different from control. Net acid excretion was still increased (P less than 0.05), urine flow rate was less (P less than 0.01) and urinary osmolality still increased (P less than 0.05). 4. There were no differences in arterial blood gases nor in pH of four fetuses which died during or shortly after infusion of acid. However, prior to acid infusion they were already excreting significantly greater amounts of phosphate (P less than 0.01), ammonium and titratable acid (P less than 0.02). Thus the fetal kidney responds to a metabolic acidosis by excreting more acid and by generating more bicarbonate, but this response is limited. © 1988 The Physiological Society

DOI 10.1113/jphysiol.1988.sp016950
Citations Scopus - 13
Co-authors E Lumbers
1988 Hill KJ, Lumbers ER, Elbourne I, 'The actions of cortisol on fetal renal function', Journal of Developmental Physiology, 10 85-96 (1988)

Renal function was studied in 6 fetal sheep, aged 126-135 days, before and after 3 injection of 15 mg of cortisol given at intervals of 12 h. Cortisol caused a significant rise in... [more]

Renal function was studied in 6 fetal sheep, aged 126-135 days, before and after 3 injection of 15 mg of cortisol given at intervals of 12 h. Cortisol caused a significant rise in both renal blood flow (P < 0.05) and glomerular filtration rate (P < 0.005), and in urine flow rate (P < 0.02) but it did not consistently cause a natriuresis. The urinary pH was unchanged following cortisol treatment, but bicarbonate excretion increased. Urinary phosphate excretion was increased (P < 0.005) because of a rise in filtered phosphate and a fall in phosphate reabsorption. The titratable acid excretion increased (P < 0.005) but urinary ammonium excretion did not. The total amount of sodium reabsorbed increased after cortisol but the amount of sodium reabsorbed in the proximal tubule did not increase, so fractional reabsorption in the proximal tubule decreased from 61.7 ± 4.1% to 47.3 ± 4.2% (P=0.01). The total amount of sodium reabsorbed in the distal tubule increased and distal fractional reabsorption increased from 33.3 ± 2.4% to 47.3 ± 4.2% (P < 0.01). Cortisol may increase the capacity of the immature kidney to play a role in fluid and electrolyte homeostasis by increasing glomerular filtration rate and delivering more sodium and water to the distal nephron where the reabsorption of sodium and water can be modified independently and in accordance with need.

Citations Scopus - 28
Co-authors E Lumbers
1988 Hill KJ, Lumbers ER, 'Renal function in adult and fetal sheep', Journal of Developmental Physiology, 10 149-159 (1988)

Renal function was studied in unanaesthetised fetal sheep aged 112-120 days, 126-132 days and in adult non-pregnant ewes. Fetal sheep of less than 120 days excreted more chloride ... [more]

Renal function was studied in unanaesthetised fetal sheep aged 112-120 days, 126-132 days and in adult non-pregnant ewes. Fetal sheep of less than 120 days excreted more chloride (P < 0.01) and had a higher urinary pH (P < 0.05) and lower net acid excretion (P < 0.01) than older fetuses. The reabsorption of both chloride and bicarbonate rose sharply between 112 and 116 days. Because the fractional reabsorption of the 2 major anions of the extracellular fluid (bicarbonate and chloride) show age dependent increases, it would seem that tubular function matures later relative to the filtered load. As well older fetuses depend more on their kidneys to maintain plasma bicarbonate levels. Fetal glomerular filtration rate (GFR) was lower (1.59 ± 0.15 (SEM) ml/min per kg) than adult GFR (2.4 ± 0.2 ml/min per kg, P < 0.01). Fetal renal blood flow was significantly less (1.6 ± 0.2 ml/min per g) than adult renal blood flow (P < 0.001, 6.4 ± 0.3 ml/min per g kidney). Therefore relative to the adult, the fetal kidneys are underperfused and the filtered load/unit body mass is less, thus their excretory capacity is limited. However, other differences in fetal renal function compared with the adult i.e. excretion of more dilute urine (P < 0.01), higher rates of clearance of sodium (P < 0.05) and phosphate and a lower rate of potassium excretion (P < 0.001) may reflect the different dietary status of the adult animal compared with the fetus.

Citations Scopus - 26
Co-authors E Lumbers
1988 Smith FG, Lumbers ER, 'Changes in renal function following delivery of the lamb by caesarian section', Journal of Developmental Physiology, 10 145-148 (1988)

Six lambs were delivered by caesarean section at 139 to 145 days of gestation. Birth was associated with a rise in glomerular filtration rate from 4.81 ± 0.62 to 5.90 ± 0.74 ml/... [more]

Six lambs were delivered by caesarean section at 139 to 145 days of gestation. Birth was associated with a rise in glomerular filtration rate from 4.81 ± 0.62 to 5.90 ± 0.74 ml/min and a transient natriuresis secondary to a fall in fractional sodium reabsorption from 93.1 ± 3.94 to 88.3 ± 2.29%. This study indicates that in the immediate postnatal period, glomerulotubular balance is disturbed.

Citations Scopus - 10
Co-authors E Lumbers
1987 Lumbers ER, Stevens AD, 'The effects of frusemide, saralasin and hypotension on fetal plasma renin activity and on fetal renal function.', The Journal of Physiology, 393 479-490 (1987)

1. In eleven chronically catheterized fetal sheep aged 124-142 days, hypotension caused by infusion of sodium nitroprusside (1.6-3.3 mg/h) and competitive antagonism of angiotensi... [more]

1. In eleven chronically catheterized fetal sheep aged 124-142 days, hypotension caused by infusion of sodium nitroprusside (1.6-3.3 mg/h) and competitive antagonism of angiotensin II by saralasin (3.3 mg/h) both caused a fall in fetal urine flow (P less than 0.02 and P less than 0.05, respectively), and in sodium excretion (P less than 0.05 and P less than 0.01) because they both caused a fall in glomerular filtration rate (G.F.R., P less than 0.02 and P less than 0.01). Neither hypotension nor saralasin had any significant effect on fractional sodium reabsorption. Saralasin only caused a significant fall in systolic pressure (P = 0.05) while infusion of sodium nitroprusside caused a fall in both systolic and diastolic pressure (P less than 0.005 and P less than 0.02). 2. Frusemide (6 mg I.V) caused a marked natriuresis and diuresis (F = 24.9, P less than 0.005 and F = 30.5, P less than 0.005). This effect was maximal within 30 min. There was no change in fetal G.F.R. and there was a significant decrease in the fraction of the filtered sodium load that was reabsorbed (F = 10.44, P less than 0.0025). Fetal mean plasma renin activity (p.r.a.) rose progressively throughout (F = 9.3, P less than 0.005). When frusemide was given to fetal sheep which were hypotensive because they were infused with sodium nitroprusside, it still caused a diuresis (F = 5.73, P less than 0.025) and the fraction of the filtered sodium load that was reabsorbed decreased (F = 4.06, P less than 0.05) to a similar extent to that seen in animals given frusemide alone. On the other hand, frusemide was ineffective as a diuretic i.e. it had no effect on fractional sodium reabsorption, when given to fetal sheep which were infused with saralasin. 3. Injection of frusemide was associated with a significant rise in the diastolic pressures of hypotensive fetuses (P less than 0.05). Furthermore, when the infusion of saralasin was terminated 1.5 h after frusemide injection, blood pressure rose significantly (F = 11.19, P less than 0.0005 for systolic pressure and F = 7.15, P less than 0.005 for diastolic pressure) and p.r.a. fell (F = 4.78, P less than 0.025). 4. It is concluded that the fetal renin-angiotensin system can play a significant role in regulation of fetal blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS) © 1987 The Physiological Society

DOI 10.1113/jphysiol.1987.sp016834
Citations Scopus - 27
Co-authors E Lumbers
1987 Smith FG, Lumbers ER, 'The effect of maternal hyperglycemia on acid base balance and lung liquid production in the fetal sheep', Pediatric Research, 22 355-359 (1987)

In 10 chronically catheterized fetal sheep, the effects of 100 g of glucose infused (intravenous) to the pregnant ewe on lung liquid production and acid-base status were investiga... [more]

In 10 chronically catheterized fetal sheep, the effects of 100 g of glucose infused (intravenous) to the pregnant ewe on lung liquid production and acid-base status were investigated. Maternal and fetal hyperglycemia occurred within 15 min of the infusion of glucose. There was a significant increase in fetal PCO 2 from 41.67 ± 1.00 to 46.89 ± 1.83 mm Hg and a decrease in fetal arterial pH from 7.42 ± 0.016 to 7.33 ± 0.026 (n = 7). This acidosis was probably the result of fetal lactacidemia. There was also a decrease in fetal PO 2 (p < 0.001) following the infusion of glucose to the ewe. This, along with the acidosis, might account for the increased risk of unexplained fetal death in the diabetic pregnancy especially near term. Following the infusion of glucose to the ewe there was an increase in maternal plasma osmolality by 16 ± 3.35 mosmol/kg (n = 9) and in fetal plasma osmolality by 14 ± 2.64 mosmol/kg (n = 9; p < 0.001). Fetal lung liquid production fell from 0.195 ± 0.04 to 0.093 ± 0.02 ml/min (n = 6; p < 0.001). There was no change in the excretion of osmol by the lungs. The decreased lung liquid production was probably due to a decrease in the net movement of fluid across the pulmonary epithelium.

Citations Scopus - 3
Co-authors E Lumbers
1986 Smith FG, Lumbers ER, Kesby GJ, 'The renal response to the ingestion of fluid by the fetal sheep', Journal of Developmental Physiology, 8 259-266 (1986)
Citations Scopus - 7
Co-authors E Lumbers
1986 Stevens AD, Lumbers ER, 'Effect on maternal and fetal renal function and plasma renin activity of a high salt intake by the ewe', Journal of Developmental Physiology, 8 267-275 (1986)
Citations Scopus - 10
Co-authors E Lumbers
1986 Lumbers ER, McCloskey DI, Potter EK, Courtice GP, 'Cardiac vagal action during hypoxia in adult and fetal sheep', Journal of the Autonomic Nervous System, 16 23-34 (1986)

The effects of hypoxia on the potential for the vagus to slow the heart, and on resting heart rate, were compared in anesthetized, vagotomized adult and fetal sheep, and in a chro... [more]

The effects of hypoxia on the potential for the vagus to slow the heart, and on resting heart rate, were compared in anesthetized, vagotomized adult and fetal sheep, and in a chronically catheterized fetus in utero. In adults, the action of the cardiac vagus was potentiated at and below an arterial pO 2 in the range 13-27 mm Hg. In contrast, in the fetus and the neonate, vagal action was not potentiated as pO 2 fell through this range to 10-12 mm Hg. Below 10-12 mm Hg baseline heart rate fell markedly, and the effect of the cardiac vagus on heart rate was diminished, but its effect on pulse interval was not consistently changed. It is concluded that potentiation of vagal action during hypoxia occurs in adult but not fetal sheep and the bradycardia seen in the fetus during severe hypoxia is probably due to direct myocardial depression. © 1986.

DOI 10.1016/0165-1838(86)90049-4
Citations Scopus - 4
Co-authors E Lumbers
1986 Lumbers ER, 'Understanding the effects of drugs in pregnancy', Current Therapeutics, 27 15-27 (1986)
Co-authors E Lumbers
1986 Kesby GJ, Lumbers ER, 'Factors affecting renal handling of sodium, hydrogen ions, and bicarbonate by the fetus', American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 251 (1986)

Renal excretion of acid and reabsorption of bicarbonate was studied in 17 chronically catheterized fetal sheep aged 121-143 days. The rates of excretion of titratable acid (0.16-6... [more]

Renal excretion of acid and reabsorption of bicarbonate was studied in 17 chronically catheterized fetal sheep aged 121-143 days. The rates of excretion of titratable acid (0.16-6.2 µmol/min) and ammonium (1.2-9.7 µmol/min) were variable. Urinary phosphate excretion was significantly greater (P < 0.001) than the excretion of titratable acid. Of the filtered bicarbonate load 80-100% was reabsorbed. In 9 of the 17 fetuses net acid excretion was positive. Bicarbonate, sodium, and chloride reabsorption were related to glomerular filtration rate (GFR) (P < 0.0005). The increase of GFR results in an increase in the excretion of titratable acid (P < 0.001), phosphate (P < 0.0005), and ammonium (P < 0.001). These relationships could accound for the age-dependent increase in renal excretion of acid (P < 0.0005), ammonium (P < 0.025), and bicarbonate reasorption (P < 0.0005). Arterial pH affected the rates of excretion of titratable acid (P < 0.005), ammonium ions (P < 0.05), and net acid (P < 0.025). It is concluded that the fetal kidney can excrete protons and generate bicarbonate. This ability increases with age due mainly to the concomitant increase in GFR.

Citations Scopus - 11
Co-authors E Lumbers
1985 Lumbers ER, Smith FG, Stevens AD, 'Measurement of net transplacental transfer of fluid to the fetal sheep.', The Journal of Physiology, 364 289-299 (1985)

If fetal drinking activity is prevented and it is assumed that in the latter third of gestation the fetus is capable of maintaining itself in fluid balance, then the net amount of... [more]

If fetal drinking activity is prevented and it is assumed that in the latter third of gestation the fetus is capable of maintaining itself in fluid balance, then the net amount of fluid gained across the placenta by the fetus is equal to the amount of fluid lost from the fetus, by routes other than the placenta, plus fluid deposited in growing tissues minus the amount of water produced as a result of oxidative metabolism. Net transplacental transfer of fluid to the fetus over a 3 h period was measured in eight chronically catheterized fetal sheep in which drinking activity was prevented by ligating the oesophagus. Urine and lung liquid flow rates were measured. In the latter third of gestation, these are the only significant sources of fluid loss from these fetuses during the 3 h experimental period. Water produced as a result of oxidative metabolism was calculated, as was the amount of fluid deposited in growing tissues during the course of the experiment. The weight of the fetus at the beginning of the experiment and the change in weight that occurred during the experiment was calculated by measuring the weight of the fetus at death (within 30 h) and applying an equation which describes the body weight-gestation age relationship for merino sheep. Net transplacental fluid transfer was 0.40 +/- 0.09 ml min-1 kg-1 (range 0.30-0.54 ml min-1 kg-1). Fetal urine flow rate averaged 0.30 +/- 0.11 ml min-1 kg-1. It was 72.8 +/- 10.0% of the volumes used to calculate net transplacental fluid transfer to the fetus. Lung liquid flow rate was 0.079 +/- 0.039 ml min-1 kg-1. It was 20.2 +/- 9.2% of the volumes used to calculate net fluid intake. The amount of fluid deposited as a result of tissue growth was 0.023 +/- 0.001 ml min-1 kg-1; it was 5.94 +/- 1.1% of the volumes used in the equation, while the production of water as a result of metabolism was 3.9 X 10(-3) ml min-1 kg-1 (Conrad & Faber, 1977) and constituted 1.01 +/- 0.22% of the volumes used in the equation. This method of measuring net transplacental fluid transfer to the fetus can be used to measure fetal fluid intake over relatively short periods of time. It also means that the effects of disturbances in maternal fluid and electrolyte balance on fluid transfer to the fetus can be studied and quantitated. © 1985 The Physiological Society

DOI 10.1113/jphysiol.1985.sp015745
Citations Scopus - 40
Co-authors E Lumbers
1985 Caine AC, Lumbers ER, Reid IA, 'The effects and interactions of angiotensin and vasopressin on the heart of unanaesthetized sheep.', The Journal of Physiology, 367 1-11 (1985)

The effects of infusions of angiotensin and vasopressin, in stepwise concentrations, on the cardiac baroreflex and on cardiac output were studied in seven adult unanaesthetized sh... [more]

The effects of infusions of angiotensin and vasopressin, in stepwise concentrations, on the cardiac baroreflex and on cardiac output were studied in seven adult unanaesthetized sheep and compared with those obtained with infusions of phenylephrine. Six animals were treated with the beta-adrenoceptor blocking drug, propranolol (in order to inhibit the effects of the sympathetic nervous system on the heart). One animal was not treated with propranolol. In those animals in which arterial pressure increased during infusion of vasopressin, the slope of the systolic pressure-pulse interval relation was greater than that seen when phenylephrine was used to increase arterial pressure. Compared with the cardiac response to pressor doses of phenylephrine, infusions of angiotensin were associated with a lesser degree of cardiac slowing and a lesser reduction in cardiac output. The effects of combined infusions of angiotensin and vasopressin on the cardiac baroreflex were studied. In five sheep which were infused with a pressor dose of angiotensin (1.1 microgram/min), the stimulatory effect of vasopressin (1.0 u./min) on pulse interval and its depressant effect on cardiac output were attenuated. In seven sheep infused with 0.5 u./min of vasopressin, I.V. infusion of angiotensin (0.2-5.0 micrograms), produced a progressive decrease in pulse interval and increase in cardiac output as the dose was increased. Therefore, angiotensin can offset the cardioinhibitory effects of vasopressin. Since cardiac sympathetic activity was blocked and neither drug has any direct chronotropic effect on the heart, it would appear that these interactions between the two drugs affect the cardiac vagus either at a peripheral or central level. © 1985 The Physiological Society

DOI 10.1113/jphysiol.1985.sp015810
Citations Scopus - 15
Co-authors E Lumbers
1985 Stevens AD, Lumbers ER, 'The effect of maternal fluid intake on the volume and composition of fetal urine', Journal of Developmental Physiology, 7 161-166 (1985)

The effects on fetal renal function of restricting maternal water intake to 1 1/day for 6 days was investigated in 7 chronically-catheterized fetuses (gestation age 118-131 days).... [more]

The effects on fetal renal function of restricting maternal water intake to 1 1/day for 6 days was investigated in 7 chronically-catheterized fetuses (gestation age 118-131 days). Restriction of water intake caused a significant decrease in maternal urine flow rate and significant increases in maternal plasma and urinary osmolality. Fetal renal function was investigated on the third and sixth days of the period of restricted maternal intake of water. Urine flow rate from the fetus was depressed significantly, and urinary osmolality increased significantly. The glomerular filtration rate remained unchanged, and free water clearance was decreased. These changes indicate increased water reabsorption in the distal parts of the nephron, probably consequent upon increased circulating levels of antidiuretic hormone. In 3 fetuses whose mothers subsequently had free access to water, these changes in urine flow rate and free water clearance that occurred during water restriction were reversed. There was an inverse correlation between maternal plasma osmolality and fetal free water clearance correlated for glomerular filtration rate. It is concluded that when water intake by a pregnant animal is restricted, the availability of water to the fetus is reduced and fetal sheep respond by producing a concentrated urine.

Citations Scopus - 20
Co-authors E Lumbers
1985 Potter EK, Parker P, Caine AC, Lumbers ER, 'Potentiation of cardiac vagal action by cold', Clinical Science, 68 165-169 (1985)

The effect of cold on vagal action at the heart was studied in sheep, dogs and an isolated guinea pig atrial preparation. During cardiac output measurements in unanaesthetized she... [more]

The effect of cold on vagal action at the heart was studied in sheep, dogs and an isolated guinea pig atrial preparation. During cardiac output measurements in unanaesthetized sheep, by the thermodilution method, bradycardia was evoked on injection of cold indicator in eight of 12 sheep studied. This bradycardia was consistently evoked when blood pressure was increased, but not at normal blood pressure levels. In the guinea pig atrial preparation, which has one vagus nerve attached, bradycardia was evoked by electrical stimulation of the vagus nerve. When the preparation was cooled this bradycardia was potentiated. In anaesthetized dogs, the cut peripheral end of one vagus was stimulated electrically at different frequencies. The linear relationship between pulse interval and vagal frequency was then compared at deep body temperatures of 35, 37, 39 and 41°C. This comparison showed that the vagus prolonged pulse interval more effectively when the animal was cool (35°C) than when it was warm (41°C).

Citations Scopus - 2
Co-authors E Lumbers
1984 Courtice GP, Kwong TE, Lumbers ER, Potter EK, 'Excitation of the cardiac vagus by vasopressin in mammals.', The Journal of Physiology, 354 547-556 (1984)

In unanaesthetized sheep, the sensitivity of the baroreceptor-cardio-inhibitory reflex was greater when intravenous vasopressin was used to raise blood pressure, than when intrave... [more]

In unanaesthetized sheep, the sensitivity of the baroreceptor-cardio-inhibitory reflex was greater when intravenous vasopressin was used to raise blood pressure, than when intravenous phenylephrine was used to raise blood pressure. This difference was still evident in animals in which beta-adrenergic blockade had been carried out using propranolol. In the presence of combined beta-adrenergic and muscarinic blockade, a direct negative chronotropic effect of intravenous vasopressin could not be demonstrated. It was concluded, therefore, that intravenous vasopressin enhanced cardiac vagal tone. This effect of vasopressin on efferent cardiac vagal tone was confirmed directly in anaesthetized dogs by recording from single cardiac vagal efferent fibres. Furthermore, recordings from single carotid sinus baroreceptor fibres did not demonstrate a direct action of vasopressin on the sensitivity of the baroreceptors. However, the pressor effect of vasopressin is associated with a greater increase in efferent cardiac vagal discharge than that seen when equipressor doses of phenylephrine are given, or when blood pressure is raised by a similar amount by inflation of an intra-aortic balloon. Studies in isolated guinea-pig atrial preparations and in anaesthetized rabbits and dogs, revealed no consistent peripheral action of vasopressin on the action of the vagus at the heart. © 1984 The Physiological Society

DOI 10.1113/jphysiol.1984.sp015392
Citations Scopus - 14
Co-authors E Lumbers
1984 Lumbers ER, 'A brief review of fetal renal function', Journal of Developmental Physiology, 6 1-10 (1984)
Citations Scopus - 18
Co-authors E Lumbers
1983 Lumbers ER, Stevens AD, 'Changes in fetal renal function in response to infusions of a hyperosmotic solution of mannitol to the ewe.', The Journal of Physiology, 343 439-446 (1983)

In six pregnant ewes a reduction in transplacental water transfer was produced by increasing maternal osmolality (by infusion of 180 g of mannitol in 500 ml of 0.15 M-sodium chlor... [more]

In six pregnant ewes a reduction in transplacental water transfer was produced by increasing maternal osmolality (by infusion of 180 g of mannitol in 500 ml of 0.15 M-sodium chloride) and the fetal renal responses to this reduction in water transfer were studied. These responses were compared with the renal responses of five other chronically catheterized fetal lambs whose mothers received I.V. infusions of 500 ml of 0.15 M-sodium chloride. Intravenous infusion of 500 ml of 0.15 M-sodium chloride to the ewe produced no changes in fetal plasma sodium, potassium or plasma renin activity and had no effect on fetal renal function. After I.V. infusion of mannitol to the ewe, fetal urinary flow rate fell from control levels of 0.69 +/- 0.12 ml/min to 0.32 +/- 0.04 ml/min (S.E. of mean, P less than 0.006). This fall in urinary flow rate was due to increased water reabsorption because there was no change in glomerular filtration rate and osmolar clearance. Fetal urinary sodium excretion increased from 16.2 +/- 2.0 mumol/min, to 34.2 +/- 6.9 mumol/min (S.E. of mean, P less than 0.04). This increase in fetal urinary sodium excretion was due to a fall in the fractional reabsorption of sodium which was related to this rise in fetal plasma sodium levels that occurred following infusion of mannitol to the ewe. The increases in fetal plasma sodium levels were also associated with reductions in fetal plasma renin activity. © 1983 The Physiological Society

DOI 10.1113/jphysiol.1983.sp014902
Citations Scopus - 60
Co-authors E Lumbers
1983 Lumbers ER, Potter EK, 'Inhibition of the vagal component of the baroreceptor-cardioinhibitory reflex by angiotensin III in dogs and sheep.', The Journal of Physiology, 336 83-89 (1983)

Angiotensin II inhibits baroreceptor-evoked activity in cardiac vagal motoneurones. Because angiotensin III [( des-1-Asp ]angiotensin II) is a less potent pressor agent than angio... [more]

Angiotensin II inhibits baroreceptor-evoked activity in cardiac vagal motoneurones. Because angiotensin III [( des-1-Asp ]angiotensin II) is a less potent pressor agent than angiotensin II, and has been reported not to share some of the actions of angiotensin II within the central nervous system, its influence on central vagal pathways was examined here. In unanaesthetized sheep equipressor doses of angiotensins II and III similarly inhibited the baroreceptor-cardioinhibitory reflex, a reflex which is almost wholly dependent on cardiac vagal activity. In anaesthetized dogs, equipressor doses of angiotensin II and III were equally effective in inhibiting the cardiac vagal activity usually evoked by rises in arterial pressure. This was established by direct recordings of activity in single cardiac vagal efferent nerve fibres. Direct recordings from single baroreceptor nerves in anaesthetized dogs showed that the angiotensins do not depress the receptor responses to elevations in blood pressure. It is concluded that equipressor doses of angiotensin III and angiotensin II inhibit central vagal pathways to the same extent. © 1983 The Physiological Society

DOI 10.1113/jphysiol.1983.sp014568
Citations Scopus - 15
Co-authors E Lumbers
1982 Lumbers ER, Potter EK, 'The effects of vasoactive peptides on the carotid cardiac baroreflex', Clinical and Experimental Pharmacology and Physiology, 9 45-49 (1982)

In unanaesthetized sheep, transitory hypertension caused by intravenous angiotensin II and angiotensin III is not associated with a progressive increase in pulse interval, while h... [more]

In unanaesthetized sheep, transitory hypertension caused by intravenous angiotensin II and angiotensin III is not associated with a progressive increase in pulse interval, while hypertension caused by intravenous vasopressin produces a progressive increase in pulse interval. Experiments in anaesthetized dogs showed that the three peptides do not alter the sensitivity of the carotid sinus baroreceptors. When arterial pressure was increased by angiotensin II and III, cardiac vagal efferent discharge did not increase as much as it did when blood pressure was raised by intravenous phenylephrine or inflation of an intra-aortic balloon - often vagal discharge did not increase at all, or even fell. Vasopressin on the other hand produced a sustained and marked increase in cardiac vagal efferent nerve activity; this was in excess of the increase evoked when other agents were used to raise blood pressure. Thus the three peptides can centrally modulate vagal control of heart rate.

Citations Scopus - 9
Co-authors E Lumbers
1981 Lee WB, Lumbers ER, 'ANGIOTENSIN AND THE CARDIAC BAROREFLEX RESPONSE TO PHENYLEPHRINE', Clinical and Experimental Pharmacology and Physiology, 8 109-117 (1981)

1. In adult conscious sheep the pressor actions of infused angiotensin II were prevented by the concomitant intravenous infusions of sodium nitroprusside. The effect of such intra... [more]

1. In adult conscious sheep the pressor actions of infused angiotensin II were prevented by the concomitant intravenous infusions of sodium nitroprusside. The effect of such intravenous infusions of angiotensin II on the cardiac baroreflex response to transient rises in arterial pressure caused by intravenous phenylephrine was studied. 2. Intravenous infusion of angiotensin II caused a reduction in pulse interval in the absence of any change in arterial pressure. It also caused a reduction in baroreflex sensitivity measured by determining the relation between pulse interval and systolic pressure during the rise in pressure caused by injection of phenylephrine. 3. After administration of the converting enzyme inhibitor (captopril) the mean baroreflex sensitivity of 3 of 4 pregnant ewes increased. 4. It is concluded that high levels of angiotensin II can modify the cardiac baroreceptor reflex response so that the heart rate is inappropriately high for a given systolic pressure and that it reduces the sensitivity of the cardiac baroreflex response to transient changes in arterial pressure. Copyright © 1981, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1440-1681.1981.tb00141.x
Citations Scopus - 30
Co-authors E Lumbers
1981 Lumbers ER, Reid IA, 'THE CARDIOVASCULAR EFFECTS OF INTRA VERTEBRAL ANGIOTENSIN II BEFORE AND AFTER TREATMENT WITH CLONIDINE', Clinical and Experimental Pharmacology and Physiology, 8 531-535 (1981)

1. In anaesthetized mongrel dogs it was shown that intravertebral infusions of angiotensin II (2¿4 ng/kg per min) increased mean arterial pressure by causing an increase in cardi... [more]

1. In anaesthetized mongrel dogs it was shown that intravertebral infusions of angiotensin II (2¿4 ng/kg per min) increased mean arterial pressure by causing an increase in cardiac output, while infusions of 10 ng/kg per min increased mean arterial pressure through an effect on peripheral resistance. After intravenous clonidine, intravertebral angiotensin no longer had any stimulatory effect on cardiac output, but arterial pressure still increased to the same extent. 2. It is concluded that intravertebral angiotensin can increase arterial pressure by increasing either cardiac output or peripheral resistance. The effects of intravertebral angiotensin on cardiac output can be reduced by concomitant stimulation of baroreflex pathways but its effects on peripheral resistance are not so readily antagonized. Copyright © 1981, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1440-1681.1981.tb00762.x
Citations Scopus - 1
Co-authors E Lumbers
1981 Alexander IE, Lumbers ER, 'The effects of angiotensin on respiratory patterns of anaesthetized dogs', Respiration Physiology, 46 261-270 (1981)

The effects of a pressor dose of angiotensin II on the respiratory pattern of chloralose anaesthetized mongrel dogs was studied. In addition, since the hypertensive action of angi... [more]

The effects of a pressor dose of angiotensin II on the respiratory pattern of chloralose anaesthetized mongrel dogs was studied. In addition, since the hypertensive action of angiotensin II stimulates baroreflex pathways, the effects on breathing of baroreceptor stimulation were examined using aortic balloon inflation and i.v. phenylephrine. In the baroreceptor-denervated dog, i.v. angiotensin II was associated with a reduction in both inspiratory and expiratory time while both inspiration and expiration proceeded more quickly. Thus breathing became deeper and more rapid. Most of these effects of angiotensin II were opposite to the effects of hypertension caused by phenylephrine and aortic balloon inflation. These two forms of hypertension caused an increased in inspiratory and expiratory time, a decrease in the rate at which inspiration proceeded and a fall in tidal volume. These effects were not seen in baroreceptor denervated animals. In the intact dog angiotensin II caused a marked vagal dependent fall in tidal volume and inspiratory time while the rates at which inspiration and expiration proceeded wre unaffected. It is concluded that angiotensin II has three independent effects on respiration. These are a respiratory depressant effect due to stimulation of baroreflex pathways by its pressor action, a 'central' stimulatory effect and an effect on the vagal control of inspiratory time. © 1981.

DOI 10.1016/0034-5687(81)90126-2
Citations Scopus - 7
Co-authors E Lumbers
1981 Stevens AD, Lumbers ER, 'The relationship between plasma renin activity and renal electrolyte excretion in the fetal sheep', Journal of Developmental Physiology, 3 101-110 (1981)

In eight fetal sheep the factors influencing renal sodium excretion were determined and related to the activity of the renin-angiotensin system. There was a direct relationship be... [more]

In eight fetal sheep the factors influencing renal sodium excretion were determined and related to the activity of the renin-angiotensin system. There was a direct relationship between glomerular filtration rate (GFR) and the amount of sodium reabsorbed (P < 0.001) suggesting that glomerular tubular balance plays an important role in regulation of fetal sodium excretion. There was also a direct relationship between GFR and urinary sodium excretion (P < 0.05). Since the percentage of the filtered sodium load that was reabsorbed was inversely related to the urinary Na/K ratio, (P < 0.001), the distal convoluted tubule is actively involved in the regulation of renal sodium excretion. There was no relationship between plasma renin activity and plasma sodium, and plasma osmolality or mean arterial pressure. There was however an inverse relationship between urinary sodium excretion and plasma renin activity, similar to that seen in adult animals (Vander & Miller, 1964) and between log plasma renin activity and GFR (P < 0.001). These experiments do not distinguish between a possible effect of angiotensin on GFR and hence renal sodium excretion, and the possible effects of a variable GFR on distal tubular sodium delivery and hence renin secretion. However they do show that the fetal renin-angiotensin system like the adult renin-angiotensin system is closely linked to those renal factors that influence renal sodium excretion.

Citations Scopus - 9
Co-authors E Lumbers
1980 Lee WB, Ismay MJ, Lumbers ER, 'Mechanisms by which angiotensin II affects the heart rate of the conscious sheep', Circulation Research, 47 286-292 (1980)

Intravenous infusion of angiotensin II were given to conscious sheep. During these infusions, the pressor action of angiotensin was antagonized by concomitant infusion of sodium n... [more]

Intravenous infusion of angiotensin II were given to conscious sheep. During these infusions, the pressor action of angiotensin was antagonized by concomitant infusion of sodium nitroprusside. Under these conditions, angiotensin produced a dose-dependent tachycardia. This dose-dependent tachycardia was not affected by propranolol and therefore it was not due to an action of angiotensin or sympathoadrenal mechanisms. The dose-dependent tachycardia was reduced by atropine, and abolished by increases in systolic pressure. We conclude that iv infusions of angiotensin cause a central, dose-dependent reduction in vagal tone. This action is normally antagonized by the baroreceptor reflex response to the hypertensive action of angiotensin. Therefore, in those conditions in which endogenous angiotensin production is increased and blood pressure is not elevated (e.g., sodium deficiency and pregnancy), angiotensin may influence heart rate.

Citations Scopus - 104
Co-authors E Lumbers
1980 Lumbers ER, Stevens AD, 'Factors influencing glomerular filtration rate in the fetal lamb [proceedings]', Journal of Physiology, 298 (1980)
Citations Scopus - 3
Co-authors E Lumbers
1980 Lumbers ER, Stevens AD, Alexander G, Stevens D, 'The cardiovascular responses of conscious newborn lambs treated in utero with 6-hydroxydopamine', Journal of Developmental Physiology, 2 139-149 (1980)

Fourteen fetal sheep were treated in utero with a single intramuscular injection or three to four injections or three to four injections of 6-hydroxydopamine. After birth the card... [more]

Fourteen fetal sheep were treated in utero with a single intramuscular injection or three to four injections or three to four injections of 6-hydroxydopamine. After birth the cardiovascular responses of these lambs to adrenergic drugs were studied and compared with the cardiovascular responses of untreated newborn lambs. Lambs which received three to four injections of 6-hydroxydopamine were more sensitive to the pressor actins of noradrenaline and phenylephrine than were control lambs or lambs which received a single injection of 6-hydroxydopamine. The supersensitivity to noradrenaline persisted in multiple treatment lambs until at least 5 months of age. Lambs which received multiple injections of 6-hydroxydopamine were also subsensitive to the pressor action of tyramine. The sensitivity to the pressor actions of noradrenaline and phenylephrine in lambs which received a single injection of 6-hydroxydopamine lay between that of control and multiple treatment groups. Despite the pharmacological evidence of impairment of sympathetic innervation of peripheral blood vessels plus a lack of responsiveness of these lambs to a-adrenergic blockade with phentolamine, treated lambs had arterial pressures and heart rates similar to control lambs. As well, treated lambs showed no impairment in their ability to reflexly regulate heart rate in response to changes in arterial pressure, which is consistent with the recently reported vagal control of the cardiac baroreceptor reflex.

Citations Scopus - 3
Co-authors E Lumbers
1979 Lumbers ER, Lewes JL, 'The actions of vasoactive drugs on fetal and maternal plasma renin activity', Biology of the Neonate, 35 23-32 (1979)

The association between fetal arterial pressure and fetal plasma renin activity (PRA) was studied in 30 fetal lambs prepared acutely, but studied in utero. There was a negative co... [more]

The association between fetal arterial pressure and fetal plasma renin activity (PRA) was studied in 30 fetal lambs prepared acutely, but studied in utero. There was a negative correlation between resting fetal arterial pressure and resting fetal PRA (p < 0.05). Fetal hypotension caused by intravenous infusion of sodium nitroprusside was associated with increases in fetal PRA. Fetal hypertension caused by intravenous infusion of phenylephrine to the fetus was associated with a decrease in fetal PRA. Maternal hypotension caused by infusion of sodium nitroprusside to the mother, and maternal hypertension caused by maternal infusion of phenylephrine caused an increase in fetal blood pressure and a fall in fetal PRA. It is concluded that the hypertensive response of the fetus to these changes in maternal blood pressure was not initiated by the fetal renin-angiotensin system. Isoprenaline caused a raise in fetal PRA. In 11 of 28 infusions this increase in fetal PRA occurred even though diastolic pressure was increased. It is concluded that there is a ß-adrenergic receptor in the fetal kidney which can release renin. The increase in fetal PRA with intravenous isoprenaline was blocked by propranolol. Infusions of adrenaline were not associated with increases in fetal PRA.

Citations Scopus - 34
Co-authors E Lumbers
1979 Ismay MJ, Lumbers ER, Stevens AD, 'The action of angiotensin II on the baroreflex response of the conscious ewe and the conscious fetus.', The Journal of Physiology, 288 467-479 (1979)

1. In conscious non-pregnant and pregnant ewes and in chronic fetal lamb preparations, the beat by beat relationship between pulse interval and systolic pressure was studied durin... [more]

1. In conscious non-pregnant and pregnant ewes and in chronic fetal lamb preparations, the beat by beat relationship between pulse interval and systolic pressure was studied during acute elevations in arterial pressure induced by phenylephrine. Baroreflex sensitivity, which was defined as the slope of the pressure-pulse interval relationship when phenylephrine was used to raise pressure, was abolished by atropine and increased by propranolol. Baroreflex sensitivity was less in pregnant ewes and in foetal lambs compared with non-pregnant ewes. 2. These findings suggest that the vagus nerve is responsible for the reflex bradycardia that occurs in the foetus and the ewe when arterial pressure is increased. 3. In both fetal and adult sheep, actue hypertension due to I.V. injection of angiotensin II was not associated with a consistent and progressive bradycardia, such as was seen with acute hypertension caused by phenylephrine. Angiotensin II has no direct chronotropic effect on heart rate in either the adult or the fetus. 4. No linear relationship between arterial pressure and pulse interval was seen when angiotensin II was used to raise pressure in sheep which were treated with propranolol. Therefore the lack of cardiac slowing with pressor doses of angiotensin II was not due to concomitant activation of the sympathoadrenal system. 5. It is concluded that in both fetal and adult sheep angiotensin II reduces the increase in vagal tone which is responsible for slowing of heart rate in response to acute rises in arterial pressure. © 1979 The Physiological Society

DOI 10.1113/jphysiol.1979.sp012708
Citations Scopus - 78
Co-authors E Lumbers
1979 Lumbers ER, McCloskey DI, Potter EK, 'Inhibition by angiotensin II of baroreceptor-evoked activity in cardiac vagal efferent nerves in the dog.', The Journal of Physiology, 294 69-80 (1979)

1. Action potentials were recorded in single baroreceptor fibres dissected from the carotid sinus nerves in dogs during increases in blood pressure caused by I.V. injection of ang... [more]

1. Action potentials were recorded in single baroreceptor fibres dissected from the carotid sinus nerves in dogs during increases in blood pressure caused by I.V. injection of angiotensin II, and by I.V. injection of phenylephrine or inflation of an aortic balloon. Action potentials were recorded in single cardiac efferent fibres dissected from the right cervical vagus nerve in other dogs during increases in blood pressure caused by angiotensin II, and by phenylephrine or by inflation of an aortic balloon. 2. There was no difference in the discharge frequency of single carotid sinus baroreceptor fibres at any blood pressure when phenylephrine, balloon inflation, or angiotensin II were used to raise the pressure. 3. Activity in single cardiac vagal efferent fibres was increased when blood pressure was increased by phenylephrine or by inflation of an aortic balloon. However, when blood pressure rose by a comparable amount in response to angiotensin II, vagal firing decreased (three fibres), was little changed from control levels (four fibres), or increased less than it did in response to phenylephrine (one fibre). 4. It is concluded that while angiotensin II has no effect on baroreceptor sensitivity, it does inhibit vagal discharge which is evoked by stimulation of arterial baroreceptors. © 1979 The Physiological Society

DOI 10.1113/jphysiol.1979.sp012915
Citations Scopus - 156
Co-authors E Lumbers
1979 Potter EK, Lumbers ER, McCloskey DI, 'Inhibition of cardiac vagal efferent nerve activity by intravenous administration of angiotensin II', Clinical and Experimental Pharmacology and Physiology, 6 675-676 (1979)
Co-authors E Lumbers
1978 Lumbers ER, Reid GC, 'The actions of vasoactive compounds in the foetus and the effect of perfusion through the placenta on their biological activity', Australian Journal of Experimental Biology and Medical Science, 56 11-24 (1978)

In acute experiments on the in utero foetal lamb, angiotensin II was a more potent pressor agent than either noradrenaline or adrenaline, and the response to angiotensin II was no... [more]

In acute experiments on the in utero foetal lamb, angiotensin II was a more potent pressor agent than either noradrenaline or adrenaline, and the response to angiotensin II was not consistently modified by the combined administration of a- and ß-adrenergic blocking agents. A significant reduction in the pressor response of the foetus to angiotensin II and noradrenaline occurred with infusion of these compounds to the foetus by the umbilical artery when compared with the response obtained with infusions of the same doses of these drugs by the umbilical vein. Moreover, the concentration of angiotensin II (pg.ml -1 ) present in the foetal circulation was less following umbilical arterial infusions compared with umbilical vein infusions of the same doses. A similar reduction in the pressor activity of adrenaline and the cardio-stimulant effect of isoprenaline occurred when these drugs were infused by the umbilical artery. It is concluded that the foetus, like the adult animal, is more sensitive to angiotensin II than to catecholamines and that the biological activities of noradrenaline, angiotensin II, adrenaline and isoprenaline are reduced by perfusion through the foetal placenta.

Citations Scopus - 13
Co-authors E Lumbers
1977 Lumbers ER, Lee-Lewis J, 'The effects of ß and a adrenergic compounds on the release of renin from the foetal kidney', Australian and New Zealand Journal of Medicine, 7 446 (1977)
Co-authors E Lumbers
1977 Lumbers ER, Reid GC, 'Effects of vaginal delivery and caesarian section on plasma renin activity and angiotensin ii levels in human umbilical cord blood', Neonatology, 31 127-134 (1977)

High levels of angiotensin II were found in umbilical venous blood of babies delivered vaginally (40.3 pgTml < sup > -1 < /sup > ) and vaginally with epidural anaesthesia (66.8 pg... [more]

High levels of angiotensin II were found in umbilical venous blood of babies delivered vaginally (40.3 pgTml < sup > -1 < /sup > ) and vaginally with epidural anaesthesia (66.8 pg-ml < sup > -1 < /sup > ); low levels of angiotensin II were found in umbilical venous blood of babies delivered by Caesarian section (7.5 pg¿ml < sup > -1 < /sup > ) and in the peripheral blood of normal adults (7.92 pg ml < sup > -1 < /sup > ). There were no significant differences between these groups in the levels of plasma renin activity (PRA), although the mean values of PRA showed trends similar to those described for angiotensin II. It is suggested that the increase in PRA may account, in part, for the high levels in angiotensin II seen following vaginal delivery, but additional factors may also be involved. © 1977 S. Karger AG, Basel.

DOI 10.1159/000240953
Citations Scopus - 31
Co-authors E Lumbers
1974 Broughten Pipkin F, Lumbers ER, Mott JC, 'Plasma renin and angiotensin II in conscious pregnant ewes and their lambs', Journal of Physiology, 237 (1974)

To study the renin angiotensin system in unanaesthetized lambs in utero, blood was obtained through catheters previously implanted in ewe and foetus. The plasma renin concentratio... [more]

To study the renin angiotensin system in unanaesthetized lambs in utero, blood was obtained through catheters previously implanted in ewe and foetus. The plasma renin concentration was determined as the rate of formation of angiotensin I from an excess of renin substrate at pH 7.5 and 37° C. Angiotensin II was extracted from plasma. Angiotensins were measured by radioimmunoassay. The foetal plasma renin concentration was much higher than the maternal. The maternal renin fell during the first 4 post operative days. Neither foetal renin nor the ratio of foetal to maternal renin changed with gestational age or with twinning. One of a pair of twins was nephrectomized in each of two ewes. In the nephrectomized foetus the plasma renin concentration fell to the limits of sensitivity of the assay and angiotensin levels also fell. In the resting state plasma levels of angiotensin II were 47.3 ± 6.6 pg/ml. in 4 ewes and 47.4 ± 14.1 pg/ml. in 5 foetuses. The corresponding renin values were 0.87 ± 0.2 and 10.4 ± 4.2 ng/ml. hr -1 . Although the foetal renin value was 10 times the maternal, the angiotensin II concentrations were not different. Since the endogenous renin activity was greater in the foetus than the ewe it is unlikely that the relatively low levels of angiotensin II in the foetus were due to a deficiency in the production of angiotensin I. The falls of plasma renin and angiotensin II concentrations after nephrectomy indicate that maintenance of normal levels is an active foetal process. The relatively low production of angiotensin II per unit of foetal renin requires explanation. It is possible that pulmonary converting enzyme concentration is low in the foetus, pulmonary blood flow is certainly less than after birth.

Citations Scopus - 4
Co-authors E Lumbers
1974 Pipkin FB, Kirkpatrick SML, Lumbers ER, Mott JC, 'Renin and angiotensin-like levels in foetal, new-born and adult sheep', The Journal of Physiology, 241 575-588 (1974)

1. Plasma renin (measured as rate of formation of angiotensin I ng/ml.hr -1 in the presence of added substrate at pH 7·5 and 37° C) was much lower in recently nephrectomized fo... [more]

1. Plasma renin (measured as rate of formation of angiotensin I ng/ml.hr -1 in the presence of added substrate at pH 7·5 and 37° C) was much lower in recently nephrectomized foetal, new-born and older lambs than in intact siblings or other similar lambs. 2. Angiotensin II-like concentrations were measured using a superfusion technique in an extracorporeal circuit. Resting concentrations in acute experiments under anaesthesia were deduced by comparison of carotid blood of intact lambs with that from recently nephrectomized lambs. 3. Angiotensin II-like activity (mean ± S.E. of mean, 315 ± 117 pg/ml.) was readily detectable in foetal blood at 123¿138 days gestation. The highest concentrations (mean ± S.E. of mean 839 ± 96 pg/ml.) were found in lambs less than 8 hr old, delivered vaginally. The lowest concentrations of angiotensin II-like activity occurred in lambs delivered by Caesarean section (mean ± S.E. of mean < 123 ± 12 pg/ml.). Concentrations declined with post-natal age. 4. Hypovolaemia as a result of haemorrhage evoked an increase in angiotensin II-like concentrations in foetus, new-born lambs and adult sheep. The greatest increase of angiotensin-like concentrations was seen in new-born lambs. This rise was associated with increase of plasma renin. 5. The rise of arterial pressure during bilateral carotid occlusion in new-born lambs was accompanied by an increase of angiotensin II-like concentration. 6. It is concluded that the renin-angiotensin system is functional and can be stimulated during intra-uterine life. The increase of angiotensin II-like concentration following parturition is probably transient and associated with the trauma of delivery. This contrasts with observations made in the rabbit which suggest that full functional maturity of the renin angiotensin system is delayed until the second week of life. © 1974 The Physiological Society

DOI 10.1113/jphysiol.1974.sp010672
Citations Scopus - 70
Co-authors E Lumbers
1974 Pipkin FB, Lumbers ER, Mott JC, 'Factors influencing plasma renin and angiotensin II in the conscious pregnant ewe and its foetus', The Journal of Physiology, 243 619-636 (1974)

1. Plasma renin (measured in the presence of additional substrate) was significantly higher (10·7 ± 1·1 S.E. of mean ng/ml.hr) in foetal lambs of 111¿144 days gestation age (... [more]

1. Plasma renin (measured in the presence of additional substrate) was significantly higher (10·7 ± 1·1 S.E. of mean ng/ml.hr) in foetal lambs of 111¿144 days gestation age (full term 147 days) than in their mothers (1·5 ± 0·2 ng/ml.hr S.E. of mean, P < 0·001) but plasma angiotensin II concentrations were in the same range (ewe 47·3 ± 6·6 S.E. of mean, foetus 47·4 ± 14·1 S.E. of mean pg/ml.). The endogenous velocity of renin production by foetal plasma was also greater than that of maternal plasma. 2. Foetal plasma [Na + ] (137 ± 0·8 S.E. of mean m-equiv/l.), was lower than that in the ewe (142 ± 1·5 m-equiv/l. S.E. of mean, P < 0·01). 3. Foetal plasma renin in lambs of less than 120 days gestation was lower (9·2 ± 2·7 S.E. of mean ng/ml.hr) than that in lambs of over 130 days gestation (12·6 ± 2·6 ng/ml.hr S.E. of mean, P < 0·01). Foetal plasma [K + ] (3·8 ± 0·1 S.E. of mean m-equiv/l.) was also lower in lambs of less than 120 days gestation than in those over 130 days (4·1 ± 0·1 S.E. of mean m-equiv/l., P < 0·001). 4. When small volumes of blood (= 3% of blood volume) were withdrawn from foetal lambs, plasma renin increased. The% increase of plasma renin in hypoxaemic foetal lambs was significantly less (P < 0·05) than in control lambs. At the end of 60 min hypoxaemia, arterial pressure and plasma [K + ] were significantly higher in hypoxaemic than in control foetal lambs. 5. During foetal hypoxaemia, plasma angiotensin II concentration increased concurrently with plasma renin. 6. Bilateral nephrectomy was performed in two foetal lambs. Plasma renin fell to very low levels and angiotensin II became undetectable. 7. Adrenaline (~.0·42 µg/min.kg I.V.) infused into the foetus did not alter foetal plasma renin. When adrenaline was infused into the ewe (~0·26 µg/min.kg) maternal plasma renin increase d. Maternal infusion of adrenaline raised foetal plasma renin significantly more (P < 0·05) than foetal infusion. 8. It is concluded that the foetal kidney is the major source of foetal renin in the last quarter of gestation and that renin release is stimulated by very small reductions of blood volume. Hypoxaemia does not augment renin release and cannot be responsible for high levels of renin and angiotensin associated with vaginal delivery. © 1974 The Physiological Society

DOI 10.1113/jphysiol.1974.sp010769
Citations Scopus - 66
Co-authors E Lumbers
1974 Pipkin FB, Lumbers ER, Mott JC, 'Proceedings: Effects of hypoxia on maternal and foetal renin and angiotensin II in sheep.', Journal of Physiology, 238 (1974)
Co-authors E Lumbers
1973 Lumbers ER, 'Proceedings: Renin and angiotensin II of extrarenal origin in the plasma of female rabbits.', Journal of Physiology, 234 (1973)
Citations Scopus - 4
Co-authors E Lumbers
1972 Morris BJ, Lumbers ER, 'The activation of renin in human amniotic fluid by proteolytic enzymes', BBA - Enzymology, 289 385-391 (1972)

Renin (EC 3.4.4.15) in human amniotic fluid can be activated by the proteolytic enzymes pepsin (EC 3.4.4.1) and trypsin (EC 3.4.4.4). Furthermore, activation of renin at pH 3.3-3.... [more]

Renin (EC 3.4.4.15) in human amniotic fluid can be activated by the proteolytic enzymes pepsin (EC 3.4.4.1) and trypsin (EC 3.4.4.4). Furthermore, activation of renin at pH 3.3-3.6 is due to an acid-stable factor which is inactive at physiological pH, and has properties similar to the enzyme pepsin. The possible relationship between these findings and the secretion of renin by the kidney is discussed. © 1972.

DOI 10.1016/0005-2744(72)90090-3
Citations Scopus - 115
Co-authors E Lumbers
1972 Trimper CE, Lumbers ER, 'The renin-angiotensin system in foetal lambs', Pflügers Archiv European Journal of Physiology, 336 1-10 (1972)

Release of renin from the kidney in response to administration of frusemide was studied in foetal lambs, pregnant ewes and non-pregnant ewes. Plasma renin concentration rose to a ... [more]

Release of renin from the kidney in response to administration of frusemide was studied in foetal lambs, pregnant ewes and non-pregnant ewes. Plasma renin concentration rose to a greater extent in the foetus as compared with adult animals. The foetal kidney was capable of releasing renin at 110 days gestation. The greater responsiveness of the foetal kidney to natriuretic administration in terms of renin release may indicate a role for the renin angiotensin system in the maintenance of foetal circulatory homeostasis. © 1972 Springer-Verlag.

DOI 10.1007/BF00589136
Citations Scopus - 36
Co-authors E Lumbers
1972 Clezy TM, Foy BN, Hodge RL, Lumbers ER, 'Oral contraceptives and hypertension an epidemiological survey', Heart, 34 1238-1243 (1972)

The effect of oral contraceptive medication on blood pressure was studied in 74 young married women over a period ranging from 3 months to 2 years. A rise in mean systolic pressur... [more]

The effect of oral contraceptive medication on blood pressure was studied in 74 young married women over a period ranging from 3 months to 2 years. A rise in mean systolic pressure of 7 mmHg and in mean diastolic pressure of i 8i mmHg was observed. The increase in systolic pressure was significant. Furthermore, the relation betw3en systolic pressure and age became significant during oral contraceptive therapy.Three out of 74 women developed sustained systolic and diastolic hypertension during oral contraceptive therapy. Women with a history of hypertension in pregnancy or with a history of parental hypertension showed a greater incidence of hypertensive visits during oral contraception.

DOI 10.1136/hrt.34.12.1238
Citations Scopus - 48
Co-authors E Lumbers
1972 Bonnin JM, Hodge RL, Lumbers ER, 'A Renin-Secreting Renal Tumour Associated with Hypertension', Australian and New Zealand Journal of Medicine, 2 178-181 (1972)

Summary: The case history of a 13-year-old boy with severe hypertension is described. On the basis of renal arteriography and estimations of plasma renin, a pre-operative diagnos... [more]

Summary: The case history of a 13-year-old boy with severe hypertension is described. On the basis of renal arteriography and estimations of plasma renin, a pre-operative diagnosis of a renin-secreting tumour was made. After the affected kidney was removed, the hypertension and the elevated plasma renin fell to normal. Copyright © 1972, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1445-5994.1972.tb03929.x
Citations Scopus - 33
Co-authors E Lumbers
1972 Skinner SL, Lumbers ER, Symonds EM, 'Analysis of changes in the renin-angiotensin system during pregnancy.', Clinical science, 42 479-488 (1972)
Citations Scopus - 115
Co-authors E Lumbers
1972 Lumbers ER, Trimper CE, 'Release of renin into the peripheral circulation of the ewe and foetus, following administration of frusemide, a natriuretic agent.', Journal of Physiology, 225 (1972)
Citations Scopus - 1
Co-authors E Lumbers
1972 Pipkin FB, Lumbers ER, Mott JC, 'Birth and angiotensin II-like activity in lambs.', Journal of Physiology, 226 (1972)
Citations Scopus - 1
Co-authors E Lumbers
1971 Lumbers ER, 'Activation of renin in human amniotic fluid by low pH.', Enzymologia, 40 329-336 (1971)
Citations Scopus - 177
Co-authors E Lumbers
1970 Lumbers ER, Whelan RF, 'Tachyphylaxis to angiotensin in man', Cardiovascular Research, 4 312-318 (1970)

Authors' synopsis: Neither angiotensin acid nor angiotensin amide infused repeatedly or continuously into the brachial artery at the elbow induced tachyphylaxis of the forearm and... [more]

Authors' synopsis: Neither angiotensin acid nor angiotensin amide infused repeatedly or continuously into the brachial artery at the elbow induced tachyphylaxis of the forearm and hand vessels. Similar results were obtained with noradrenaline and acetylcholine, whereas tachyphylaxis was readily induced to intra-arterial infusions of vasopressin. It is concluded that tachyphylaxis plays no role in the vascular response to angiotensin in normal subjects and that the reduced vascular response to angiotensin seen in patients with reno-vascular hypertension is not solely due to high concentrations of circulating angiotensin.

DOI 10.1093/cvrese/4.3.312
Citations Scopus - 2
Co-authors E Lumbers
1970 Lim YL, Lumbers ER, Walters WAW, Whelan RF, 'Effects of oestrogens on the human circulation', Journal of Obstetrics and Gynaecology of the British Commonwealth, 77 349-355 (1970)

The naturally occurring oestrogens, oestrone and oestriol, were given by intraarterial infusion into the brachial artery and by intravenous injection. No changes in blood flow thr... [more]

The naturally occurring oestrogens, oestrone and oestriol, were given by intraarterial infusion into the brachial artery and by intravenous injection. No changes in blood flow through the hand or forearm were observed with either route of administration. Intravenous injection resulted in a significant rise in blood pressure but no significant changes in heart rate or limb vascular resistance. It is suggested that this rise in blood pressure may be due to a direct action of the hormones on the heart. © 1970.

Citations Scopus - 21
Co-authors E Lumbers
1970 Lim YL, Lumbers ER, Walters WAW, Whelan RF, 'EFFECTS OF OESTROGENS ON THE HUMAN CIRCULATION', BJOG: An International Journal of Obstetrics & Gynaecology, 77 349-355 (1970)

The naturally occurring oestrogens, oestrone and oestriol, were given by intraarterial infusion into the brachial artery and by intravenous injection. No changes in blood flow thr... [more]

The naturally occurring oestrogens, oestrone and oestriol, were given by intraarterial infusion into the brachial artery and by intravenous injection. No changes in blood flow through the hand or forearm were observed with either route of administration. Intravenous injection resulted in a significant rise in blood pressure but no significant changes in heart rate or limb vascular resistance. It is suggested that this rise in blood pressure may be due to a direct action of the hormones on the heart. Copyright © 1970, Wiley Blackwell. All rights reserved

DOI 10.1111/j.1471-0528.1970.tb03531.x
Co-authors E Lumbers
1970 Lumbers ER, 'Peripheral vascular reactivity to angiotensin and noradrenaline in pregnant and non-pregnant women.', The Australian journal of experimental biology and medical science, 48 493-500 (1970)
Citations Scopus - 26
Co-authors E Lumbers
1969 Lumbers ER, Skinner SL, 'The occurrence and assay of renin in human urine.', The Australian journal of experimental biology and medical science, 47 251-262 (1969)
Citations Scopus - 11
Co-authors E Lumbers
1969 Lumbers ER, Skinner SL, 'Observations on the origin of renin in human urine.', Circulation Research, 24 689-697 (1969)
Citations Scopus - 17
Co-authors E Lumbers
1969 Skinner SL, Lumbers ER, Symonds EM, 'Alteration by oral contraceptives of normal menstrual changes in plasma renin activity, concentration and substrate.', Clinical science, 36 67-76 (1969)
Citations Scopus - 161
Co-authors E Lumbers
1968 Skinner SL, Lumbers ER, Symonds EM, 'Renin concentration in human fetal and maternal tissues', American Journal of Obstetrics and Gynecology, 101 529-533 (1968)

Expressed as relative concentration per wet weight, chorion consistently displayed the highest renin content outside of kidney among the tissues and fluids examined. Renin in post... [more]

Expressed as relative concentration per wet weight, chorion consistently displayed the highest renin content outside of kidney among the tissues and fluids examined. Renin in postmortem kidney was twelvefold more concentrated than in chorion. Mean concentration in chorion (4,420 units per gram) was fourfold that in either amniotic fluid, amnion and decidua; concentration in myometrium (47 units per gram) and maternal surface of placenta (51 units per gram) was much lower at approximately twofold that of fetal and maternal plasma. Renin concentration in chorion from the fetal surface of placenta (473 units per gram) was less than in peripheral chorion but greater than in the maternal surface of placenta. Following artificial rupture of the membranes, renin concentration in freely draining liquor did not alter during 2 to 7 hour periods. These findings suggest that chorion is the source of renin in human amniotic fluid and that decidua, by limiting outward diffusion effectively, promotes intra-amniotic accumulation. © 1968.

Citations Scopus - 123
Co-authors E Lumbers
Show 203 more journal articles

Conference (61 outputs)

Year Citation Altmetrics Link
2016 Mah B, Weatherall L, Burrows J, Blackwell C, Wadhwa P, Lumbers E, et al., 'Psychological Distress in Pregnant Australian Indigenous Women Residing in Rural and Remote New South Wales of Australia', REPRODUCTIVE SCIENCES (2016)
Co-authors Roger Smith, Julie Burrows, Kym Rae, E Lumbers, Caroline Blackwell
2016 Mohammed R, Delforce S, Wang Y, Verrills N, Lumbers E, Pringle K, 'EFFECT OF (P)RR KNOCKDOWN AND RAS INHIBITORS ON ENDOMETRIAL CANCER GROWTH', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors E Lumbers, Kirsty Pringle
2016 Mah B, Weatherall L, Burrows J, Blackwell C, Wadwha P, Lumbers ER, et al., 'Psychological Distress in pregnant Australian Indigenous women residing in rural and remote New South Wales', Conference Proceedings (2016)
Co-authors Caroline Blackwell, Julie Burrows, Kym Rae, E Lumbers
2015 Pringle K, Grimson S, Wang Y, Weatherall L, Smith R, Rae KM, et al., 'Cytokine Gene Polymorphisms in an Indigenous Australian Pregnancy Population', Reproductive Sciences (2015) [E3]
Co-authors Kym Rae, Kirsty Pringle, Roger Smith, E Lumbers, Caroline Blackwell
2015 Lumbers ER, Grimson S, Cox AJ, Pringle KJ, Burns C, Blackwell CC, Scott RJ, 'THE DISTRIBUTION OF SOME SINGLE NUCLEOTIDE POLYMORPHISMS OF THE RENIN-ANGIOTENSIN SYSTEM IN INDIGENOUS AUSTRALIANS', HYPERTENSION (2015) [E3]
Co-authors Caroline Blackwell, E Lumbers, Kirsty Pringle, Rodney Scott
2015 Wang Y, Pringle KG, Conquest A, Mitchell C, Zakar T, Lumbers ER, 'A Potential Mechanism By Which Fetal Sex Influences the Prevalence of Preterm Birth', REPRODUCTIVE SCIENCES (2015) [E3]
Co-authors E Lumbers, Kirsty Pringle
2015 Rae KM, Weatherall L, Collins C, Smith R, Lumbers ER, Pringle K, 'Maternal obesity negatively impacts on fetal maternal health and birth outcomes in an Indigenous Australian cohort', Journal of Developmental Origins of Health and Disease (2015) [E3]
Co-authors E Lumbers, Roger Smith, Clare Collins, Kirsty Pringle, Kym Rae
2015 Weatherall L, Smith R, Collins C, Rae KM, Lumbers ER, Pringle K, 'Risk factors for development of future chronic disease from an Indigenous Australian cohort', Journal of Developmental Origins of Health and Disease (2015) [E3]
Co-authors Roger Smith, E Lumbers, Clare Collins, Kym Rae
2015 Rae KM, Pringle K, Sykes S, Weatherall L, Clausen D, Smith R, et al., 'Factors affecting blood pressure and renal health in Australian Indigenous Women', Reproductive Sciences (2015) [E3]
Co-authors Caroline Blackwell, E Lumbers, Roger Smith, Kirsty Pringle, Kym Rae
2015 Pringle K, Sykes S, Weatherall L, Clausen D, Smith R, Rae KM, Lumbers E, 'Interrelationships between circulating and urinary components of the renin-angiotensin system in Indigenous pregnant women', Reproductive Sciences (2015) [E3]
Co-authors Roger Smith, E Lumbers, Kirsty Pringle, Kym Rae
2015 Smith R, Rae K, Lumbers E, Kandasamy Y, Pringle K, Weatherall L, 'Preterm birth and low birthweight in the Aboriginal and Torres Strait Islander Population', BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY (2015) [E3]
Co-authors E Lumbers, Roger Smith, Kirsty Pringle, Kym Rae
2015 Lumbers ER, Sykes SD, Weatherall L, Clausen D, Smith R, Rae K, Pringle KG, 'INTERRELATIONSHIPS BETWEEN CIRCULATING AND URINARY COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM IN INDIGENOUS PREGNANT WOMEN', HYPERTENSION (2015) [O1]
Co-authors E Lumbers, Roger Smith, Kirsty Pringle, Kym Rae
2014 Wang Y, Morris B, Roberts CT, Broughton-Pipkin F, Lumbers ER, Pringle KG, 'Effect of low oxygen on the pro-angiogenic pathways of the renin angiotensin system (RAS) in a human trophoblast cell line.', Journal of Pediatrics and Child Health (2014) [E3]
DOI 10.1111/jpc.12528
Co-authors E Lumbers, Kirsty Pringle
2014 Pringle K, Rae KM, Weatherall L, Hall S, Burns C, Smith R, et al., 'Effects of cigarette smoke and maternal inflammation in pregnancy on birth weight and gestational age at delivery in an Indigenous Australian population', Proceedings of the 57th ESA and 45th SRB Annual Conference (2014) [E3]
Co-authors Roger Smith, Caroline Blackwell, Sharron Hall, E Lumbers, Kirsty Pringle, Kym Rae
2014 Lumbers ER, Grimson S, Cox A, Pringle KG, Burns C, Blackwell CC, Scott R, 'The distribution of some nucleotide polymorphisms of the renin-angiotensin system in Indigenous Australians.', State of Heart 2014 Congress (2014) [E3]
Co-authors Caroline Blackwell, E Lumbers, Rodney Scott, Kirsty Pringle
2014 Rae KM, Pringle KG, Sykes SD, Weatherall L, Clausen D, Smith R, et al., 'Factors affecting blood pressure and renal health in young Indigenous pregnant women', State of the Heart 2014 Congress (2014) [E3]
Co-authors Kirsty Pringle, Caroline Blackwell, Roger Smith, E Lumbers, Kym Rae
2014 Pringle KG, Sykes S, Diehm C, Weatherall L, Galal M, Clausen D, et al., 'The intrarenal renin angiotensin system in pregnancy and its potential in predicting renal dysfunction and fetal kidney development in Indigenous and non-Indigenous Australian women', Abstracts of the 18th Congress of the Perinatal Society of Australia and New Zealand (PSANZ) (2014) [E3]
DOI 10.1111/jpc.12528/abstract
Co-authors Kym Rae, Roger Smith, Kirsty Pringle, E Lumbers
2014 Lumbers ER, Pringle KG, Sykes SD, Weatherall L, Clausen DC, Rae K, Smith R, 'THE INTRARENAL RENIN-ANGIOTENSIN SYSTEM (RAS) IN HUMAN PREGNANCY', HYPERTENSION (2014) [E3]
Co-authors E Lumbers, Kym Rae, Roger Smith, Kirsty Pringle
2014 Delforce SJ, Pringle KG, Wang Y, Verrills NM, Scott RJ, Lumbers ER, 'THE FUNCTIONAL ROLE OF THE ENDOMETRIAL RENIN ANGIOTENSIN SYSTEM IN ENDOMETRIAL CANCER', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2014) [E3]
Co-authors Rodney Scott, Kirsty Pringle, E Lumbers, Nikki Verrills
2013 Pringle KG, Sykes SD, Weatherall L, Clausen D, Smith R, Rae KM, Lumbers ER, 'Novel Urinary Biomarkers for Predicting Pregnancy Outcome in Indigenous and Non- Indigenous Australian Women', Published proceedings of the Fetal and Neonatal Workshop (2013) [E3]
Co-authors Roger Smith, E Lumbers, Kirsty Pringle, Kym Rae
2013 Pringle KG, Sykes SD, Weatherall L, Galal, Clausen D, Smith R, et al., 'The intrarenal renin angiotensin system in pregnancy and its potential in predicting pregnancy outcome and renal dysfunction in Indigenous and non-Indigenous Australian women', Published proceedings of the Society for Reproductive Biology (2013) [E3]
Co-authors Kirsty Pringle, E Lumbers, Roger Smith, Kym Rae
2013 Pringle K, Sykes SD, Weatherall L, Clausen D, Smith R, Rae KM, Lumbers ER, 'Novel renal biomarkers for predicting pregnancy outcome', Published proceedings of the Symposium on Vasoactive Peptides (2013) [E3]
Co-authors Roger Smith, E Lumbers, Kirsty Pringle, Kym Rae
2013 Lumbers ER, Wang Y, Pringle KG, Scott RJ, 'Expression of the renin-angiotensin system in an endometrial cancer cell line', Published proceedings of the Symposium on Vasoactive Peptides (2013) [E3]
Co-authors E Lumbers, Rodney Scott, Kirsty Pringle
2013 Rae KM, Weatherall L, Clausen D, Maxwell C, Bowman M, Milgate P, et al., 'Gomeroi gaaynggal: Empowerment of Aboriginal communities to understand health implications of research in pregnancy', Proceedings of th 12th National Rural Health Conference (2013) [E1]
Co-authors Sharron Hall, E Lumbers, Kym Rae, Maria Bowman, Roger Smith
2013 Rae KM, Lumbers ER, Pringle KG, Sykes SD, Weatherall L, Clausen D, Smith R, 'Measurement of the activity of the circulating and intrarenal renin-angiotensin system (iRAS) in pregnant and non-pregnant subjects PP036', Pregnancy Hypertension (2013)
Co-authors Roger Smith, Kirsty Pringle, Kym Rae, E Lumbers
2013 Pringle, Lumbers, Sykes, Weatherall, Clausen D, Rae KM, Smith, 'The intrarenal renin angiotensin system and pregnancy outcome.', Pregnancy Hypertension: an International Journal of Women's Cardiovascular Health (2013) [E3]
DOI 10.1016/j.preghy.2013.04.063
Co-authors E Lumbers, Kym Rae, Roger Smith, Kirsty Pringle
2013 Lumbers, Pringle, Sykes, Weatherall, Clausen D, Rae KM, Smith, 'Measurement of the activity of the circulating and intrarenal renin-angiotensin system (iRAS) in pregnant and non-pregnant subjects.', Pregnancy Hypertension: an International Journal of Women¿s Cardiovascular Health. (2013) [E3]
DOI 10.1016/j.preghy.2013.04.053
Co-authors Kym Rae, Roger Smith, E Lumbers, Kirsty Pringle
2012 Sykes SD, Lumbers ER, Pringle KG, Zhou A, Dekker GA, Roberts CT, 'Alterations in the maternal renin angiotensin system (RAS) in women who deliver preterm or small for gestational age babies', Abstracts. The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2012 (2012) [E3]
Co-authors E Lumbers, Kirsty Pringle
2012 Pringle KG, Wang Y, Lumbers ER, 'Evidence for the synthesis, secretion and uptake of prorenin in human amnion', Abstracts. The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2012 (2012) [E3]
Co-authors E Lumbers, Kirsty Pringle
2012 Eiby YA, Staunton MP, Wright LL, Lumbers ER, Colditz PPB, Lingwood BE, 'Cardiovascular and hormonal responses to hypoxic stress in the preterm piglet', Journal of Paediatrics and Child Health (2012) [E3]
Co-authors E Lumbers
2012 Rae KM, Weatherall L, Clausen D, Maxwell C, Bowman M, Milgate P, et al., 'The role of maternal renal health in an Australian Aboriginal population in fetal growth and renal development' (2012)
Co-authors Roger Smith, Maria Bowman, Sharron Hall, Kym Rae, E Lumbers
2012 Wang Y, Pringle KG, Lumbers ER, 'Effects of cAMP on sexually determined renin expression and secretion by human decidual explants', Journal of Paediatrics and Child Health (2012) [E3]
Co-authors Kirsty Pringle, E Lumbers
2012 Kim MY, Eiby YA, Lumbers ER, Boyce AC, Gibson KJ, Lingwood BE, 'Expression of adrenoceptor subtypes in the preterm pig heart', Journal of Paediatrics and Child Health (2012) [E3]
Co-authors E Lumbers
2012 Pringle KG, Wang Y, Sykes SD, Lumbers ER, 'Fetal sex affects the expression of the renin angiotensin system in intra-uterine tissues', Journal of Paediatrics and Child Health (2012) [E3]
Co-authors E Lumbers, Kirsty Pringle
2012 Sykes SD, Pringle KG, Zhou A, Dekker GA, Roberts CT, Lumbers ER, 'Fetal sex affects the renin angiotensin system and the aetiology of gestational hypertension and preeclampsia', Journal of Paediatrics and Child Health (2012) [E3]
Co-authors E Lumbers, Kirsty Pringle
2011 Mitchell CM, Sykes SD, Pringle KG, Lumbers ER, Hirst JJ, Bisits AJ, Zakar T, 'Methylation of CpG Islands in the promoters of proinflammatory and steroid receptor genes in the human amnion, decidua and placenta', Reproductive Sciences (2011) [E3]
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2011 Rae KM, Weatherall L, Hall S, Milgate P, Boyd J, Bowman M, et al., 'Tackling pregnancy outcomes ¿ the Gomeroi gaaynggal program' (2011)
Co-authors Maria Bowman, Roger Smith, Sharron Hall, Kym Rae, E Lumbers
2011 Zhou A, Dekker G, Lumbers ER, Heinemann G, North R, McCowan L, Roberts C, 'Association of the ACE A11860G single nucleotide polymorphism (SNP) and fetal sex in small for gestational age (SGA) pregnancy', Placenta (2011) [E3]
Co-authors E Lumbers
2010 Conquest AL, Pringle KG, Logan P, Mitchell MD, Lumbers ER, 'PLZF: The missing link in decidualisation?', 24th Fetal and Neonatal Physiology Workshop of Australia and New Zealand. Program and Abstracts (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2010 Mitchell CM, Bisits AM, Sykes SD, Pringle KG, Lumbers ER, Zakar T, 'CPG island methylation of proinflammatory and steroid receptor gene promoters in the human amnion', The Endocrine Society of Australia Annual Scientific Meeting Proceedings and Abstract Book (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2010 Lumbers ER, Pringle KG, Marques FZ, Hirst JJ, Markus MA, Morris BJ, et al., 'Identification of renin-angiotensin system (RAS) in human fetal membranes, decidua and placenta and the effects of gender and labour', Hypertension (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2010 Pringle KG, Zakar T, Hirst JJ, Lumbers ER, 'Evidence that the renin angiotensin system is involved in early placentation', Journal of Paediatrics and Child Health: Abstracts of the 14th Annual Congress of the Perinatal Society of Australia and New Zealand 2010 (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2010 Lumbers ER, Pringle KG, Logan PC, Mitchell MD, 'Epigenetic regulation of prorenin and other components of the decidual renin angiotensin system (RAS)', Journal of Paediatrics and Child Health: Abstracts of the 14th Annual Congress of the Perinatal Society of Australia and New Zealand 2010 (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2010 Pringle KG, Conquest AL, Mitchell CM, Zakar T, Lumbers ER, 'The Prorenin Receptor/PLZF Pathway in Human Amnion', Reproduction, Fertility and Development (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2010 Mitchell CM, Zakar T, Sykes SD, Pringle KG, Lumbers ER, 'Methylation of Genes of the Renin Angiotensin System (RAS) in Early Human Amnion', Reproduction, Fertility and Development (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2010 Marques FZ, Pringle KG, Markus MA, Conquest AL, Hirst JJ, Sarris M, et al., 'Molecular characterization of renin-angiotensin system components in human intrauterine tissues and fetal membranes from vaginal delivery and cesarean section', Reproduction, Fertility and Development (2010) [E3]
DOI 10.1016/j.placenta.2010.12.006
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2010 Sykes SD, Lumbers ER, Pringle KG, Zakar T, Dekker GA, Roberts CT, 'Predicting Gestational Hypertension and Preeclampsia from Maternal Angiotensin II and Angiotensin 1-7 Levels at 15 Weeks Gestation', Reproduction, Fertility and Development (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2010 Sykes SD, Lumbers ER, Pringle KG, Zakar T, Dekker GA, Roberts CT, 'Predicting Gestational Diabetes From Maternal Angiotensin II and Angiotensin 1-7 Levels at 15 Weeks Gestation', Reproduction, Fertility and Development (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2010 Wang Y, Pringle KG, Chen Y, Zakar T, Lumbers ER, 'Regulation of the Renin Angiotensin System (RAS) in a Trophoblast Cell Line by Cyclic Adenosine Monophosphate (CAMP) and 5'-AZA-2'-Deoxycytidine (AZA)', Reproduction, Fertility and Development (2010) [E3]
Co-authors E Lumbers, Kirsty Pringle
2009 Lumbers ER, Pringle KG, Roach DM, Mitchell CM, Hirst JJ, Markus A, et al., 'The identification and role of the intrauterine (Pro)renin/(Pro)renin receptor angiotensin system in prostaglandin synthesis in pregnancy', Reproductive Sciences (2009) [E3]
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2009 Pringle KG, Hirst JJ, Mitchell CM, Zakar T, Lumbers ER, 'The mechanism of prorenin induced PGHS-2 expression in the amnion', Reproductive Sciences (2009) [E3]
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2009 Gibson KJ, Wang Y, Boyce AC, Palliser HK, Hirst JJ, Lumbers ER, 'Effects of intrauterine growth restriction on the intrarenal renin angiotensin system in the neonatal guinea pig', Journal of Paediatrics and Child Health (2009) [E3]
DOI 10.1111/j.1440-1754.2009.01474.x
Co-authors E Lumbers, Jon Hirst, Hannah Palliser
2009 Pringle KG, Hirst JJ, Conquest AL, Mitchell CM, Zakar T, Lumbers ER, 'The role of prorenin in amnion PGHS-2 expression and the induction of labour', Journal of Paediatrics and Child Health (2009) [E3]
DOI 10.1111/j.1440-1754.2009.01474.x
Co-authors E Lumbers, Kirsty Pringle, Jon Hirst
2008 Roach DM, Lumbers ER, Mitchell CM, Hirst JJ, Zakar T, 'The identification of the intrauterine (pro)renin/(pro)renin receptor system and its role in prostaglandin synthesis in pregnancy and labour', Journal of Paediatrics and Child Health (2008) [E3]
DOI 10.1111/j.1440-1754.200801297.x
Co-authors E Lumbers, Jon Hirst
2008 Lumbers ER, Roach DM, Mitchell CM, Hirst JJ, Zakar T, 'The identification and role of the intrauterine (pro) renin/(pro)renin receptor system in prostaglandin synthesis in pregnancy', Reproductive Sciences (2008) [E3]
Co-authors E Lumbers, Jon Hirst
2008 Pringle KG, Roach DM, Mitchell CM, Hirst JJ, Zakar T, Lumbers ER, 'The intrauterine (pro)renin/(pro)renin receptor system and its role in prostaglandin synthesis during pregnancy', 51st Annual Scientific Meeting of the Endocrine Society of Australia and Society of Reproductive Biology: Meeting Proceedings and Abstract Book (2008) [E3]
Co-authors E Lumbers, Jon Hirst, Kirsty Pringle
2008 Kim M-Y, Burrell J, Kumarasamy V, Boyce A, Gibson K, Gatford K, et al., 'Sexual dimorphism of cardiac myocytes in the fetal sheep and the effects of IGF-1 treatment', The Twenty-Second Fetal and Neonatal Workshop of Australia and New Zealand Abstract Book (2008) [E3]
Co-authors E Lumbers
2007 Standen P, Lumbers ER, Kumarasamy V, Sferruzzi-Perri AN, Taylor R, Heinemann G, Roberts CT, 'Novel interactions between insulin-like growth factors (IGF) and the renin-angiotensin system (RAS) in the placenta', Journal of Paediatrics and Child Health (2007) [E3]
Co-authors E Lumbers
2007 Lumbers ER, 'Fetal fluid and electrolyte homeostasis', Healthy Start for a Healthy Life: The Wintour's Tale: An International Satellite Conference of DOHaD 2007 (2007) [E3]
Co-authors E Lumbers
2006 Lumbers ER, Standen P, Kumarasamy V, Sferruzzi-Perri AN, Taylor R, Heinemann G, Roberts CT, 'Novel effects of insulin-like growth factor (IGF)-I and -II on placental renin in the guinea pig', PLACENTA (2006)
Co-authors E Lumbers
2003 Boyce AC, Lumbers ER, Gibson KJ, Wu J, Owens PC, Owens JA, et al., 'Insulin-like growth factor I and the developing renin angiotensin system', FASEB JOURNAL (2003)
Co-authors E Lumbers
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Grants and Funding

Summary

Number of grants 24
Total funding $4,743,381

Click on a grant title below to expand the full details for that specific grant.


20161 grants / $21,745

Angiotensin system inhibitors potentiate the efficacy of bevacizumab in the treatment of cancer$21,745

Funding body: John Hunter Hospital Charitable Trust

Funding body John Hunter Hospital Charitable Trust
Project Team Professor Eugenie Lumbers, Conjoint Associate Professor Anthony Proietto, Laureate Professor Rodney Scott, Doctor Kirsty Pringle
Scheme Research Grant
Role Lead
Funding Start 2016
Funding Finish 2016
GNo G1600598
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

20151 grants / $25,222

Novel mechanisms whereby fetal sex and the maternal decidua regulates labour onset$25,222

Funding body: John Hunter Hospital Charitable Trust

Funding body John Hunter Hospital Charitable Trust
Project Team Doctor Eric Wang, Professor Eugenie Lumbers, Professor Ian Symonds
Scheme Research Grant
Role Investigator
Funding Start 2015
Funding Finish 2015
GNo G1500373
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

20143 grants / $697,870

An early indicator of renal dysfunction in Indigenous women at risk of pregnancy complications $645,358

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Doctor Kirsty Pringle, Professor Eugenie Lumbers, Associate Professor Kym Rae, Professor Fiona Broughton-Pipkin, Laureate Professor Roger Smith
Scheme Project Grant
Role Investigator
Funding Start 2014
Funding Finish 2016
GNo G1300183
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

A new therapeutic strategy for the treatment of endometriosis$27,512

Funding body: John Hunter Hospital Charitable Trust

Funding body John Hunter Hospital Charitable Trust
Project Team Doctor Eric Wang, Doctor Mohamed Galal, Doctor Kirsty Pringle, Professor Eugenie Lumbers
Scheme Research Grant
Role Investigator
Funding Start 2014
Funding Finish 2014
GNo G1400553
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

Does a novel biomarker of renal function in pregnant Indigenous Australian women predict their future renal and cardiovascular health?$25,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Professor Eugenie Lumbers, Doctor Kirsty Pringle, Associate Professor Kym Rae, Laureate Professor Roger Smith
Scheme Project Grant
Role Lead
Funding Start 2014
Funding Finish 2014
GNo G1301370
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

20134 grants / $546,868

Regulation of the placental renin-angiotensin system by microRNAs; implications for pregnancies complicated by placental insufficiency? $483,059

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Professor Eugenie Lumbers, Professor Claire Roberts, Professor Brian Morris, Professor Fiona Broughton-Pipkin
Scheme Project Grant
Role Lead
Funding Start 2013
Funding Finish 2015
GNo G1200076
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Identification of a novel urinary biomarker to identify women at risk of developing preeclampsia$23,809

Funding body: John Hunter Hospital Charitable Trust

Funding body John Hunter Hospital Charitable Trust
Project Team Doctor Kirsty Pringle, Doctor Mohamed Galal, Professor Eugenie Lumbers
Scheme Research Grant
Role Investigator
Funding Start 2013
Funding Finish 2013
GNo G1300969
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

Drugs that act on the renin-angiotensin system; repositioning their therapeutic targets to endometrial cancer$20,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Laureate Professor Rodney Scott, Professor Eugenie Lumbers
Scheme Near Miss Grant
Role Investigator
Funding Start 2013
Funding Finish 2013
GNo G1300484
Type Of Funding Internal
Category INTE
UON Y

Drugs that act on the renin-angiotensin system; respositioning their therapeutic targets to endometrial cancer$20,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Laureate Professor Rodney Scott, Professor Eugenie Lumbers
Scheme Near Miss
Role Investigator
Funding Start 2013
Funding Finish 2013
GNo G1300654
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

20125 grants / $1,928,467

Understanding the Origins of Diabetes and Kidney Disease in Aboriginal Children and Their Mothers$1,784,613

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Roger Smith, Professor Mark McLean, Professor Eugenie Lumbers, Professor Sandra Eades, Emeritus Professor John Boulton, Associate Professor Kym Rae, Professor Clare Collins
Scheme Project Grant
Role Investigator
Funding Start 2012
Funding Finish 2016
GNo G1100137
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

An integrated approach to inotropic support in preterm neonates$75,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Dr Barbara Lingwood, Conjoint Professor Ian Wright, Professor Eugenie Lumbers, Professor Paul Colditz
Scheme Project Grant
Role Investigator
Funding Start 2012
Funding Finish 2014
GNo G1101107
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Drugs that act on the renin-angiotensin system; repositioning their therapeutic targets to endometrial cancer$34,454

Funding body: John Hunter Hospital Charitable Trust

Funding body John Hunter Hospital Charitable Trust
Project Team Professor Eugenie Lumbers, Doctor Kirsty Pringle, Dr Henry Murray
Scheme Research Grant
Role Lead
Funding Start 2012
Funding Finish 2012
GNo G1200650
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

The role of the intrarenal renin angiotensin system in preeclampsia and gestational hypertension$24,400

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Kirsty Pringle, Professor Eugenie Lumbers
Scheme Project Grant
Role Investigator
Funding Start 2012
Funding Finish 2012
GNo G1101206
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

Precellys Tissue Homogeniser$10,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Roger Smith, Professor Eugenie Lumbers, Conjoint Professor Tamas Zakar, Professor Jon Hirst, Conjoint Professor Ian Wright, Doctor Gemma Madsen, Doctor Kaushik Maiti
Scheme Equipment Grant
Role Investigator
Funding Start 2012
Funding Finish 2012
GNo G1100979
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20111 grants / $25,000

Role of the renin-angiotensin system in pregnancies complicated by placental insufficiency$25,000

Funding body: John Hunter Hospital Charitable Trust

Funding body John Hunter Hospital Charitable Trust
Project Team Doctor Kirsty Pringle, Professor Eugenie Lumbers, Professor Ian Symonds
Scheme Research Grant
Role Investigator
Funding Start 2011
Funding Finish 2012
GNo G1100637
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

20095 grants / $957,859

Stress during pregnancy and the developmental origins of renal disease in aboriginal Australians$832,535

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Roger Smith, Professor Eugenie Lumbers, Conjoint Professor Caroline Blackwell, Dr Edouard Tursan d'Espaignet, Professor Pathik Wadhwa, Conjoint Associate Professor Andrew Bisits
Scheme Project Grant
Role Investigator
Funding Start 2009
Funding Finish 2011
GNo G0188884
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Novel molecular regulators of pregnancy success$60,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Professor Eugenie Lumbers
Scheme Project Grant
Role Lead
Funding Start 2009
Funding Finish 2011
GNo G0190480
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Stress during pregnancy and the developmental origins of renal disease in Aboriginal Australians$27,040

Funding body: Kidney Health Australia

Funding body Kidney Health Australia
Project Team Associate Professor Kym Rae, Laureate Professor Roger Smith, Professor Eugenie Lumbers
Scheme Medical Research Project Grants
Role Investigator
Funding Start 2009
Funding Finish 2010
GNo G0189886
Type Of Funding Aust Competitive - Non Commonwealth
Category 1NS
UON Y

The role of prorenin in the first trimester placenta: Key to pregnancy success$24,814

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Kirsty Pringle, Professor Eugenie Lumbers, Conjoint Professor Tamas Zakar
Scheme Project Grant
Role Investigator
Funding Start 2009
Funding Finish 2009
GNo G0189797
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

i-STAT 1 Blood Gas Analyser and Softron BP-98E$13,470

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Conjoint Professor Ian Wright, Professor Jon Hirst, Professor Eugenie Lumbers, Conjoint Professor Tamas Zakar, Doctor Hannah Palliser
Scheme Equipment Grant
Role Investigator
Funding Start 2009
Funding Finish 2009
GNo G0189843
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20083 grants / $520,350

The role of the intrauterine (pro) renin/(pro)renin receptor system in prostaglandin synthesis in pregnancy$468,750

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Professor Eugenie Lumbers, Conjoint Professor Tamas Zakar, Professor Jon Hirst, Professor Brian Morris
Scheme Project Grant
Role Lead
Funding Start 2008
Funding Finish 2010
GNo G0187618
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Pregnancy and reproduction research: The role of the intrauterine (pro)renin/(pro)renin receptor system in prostaglandin synthesis$42,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Professor Eugenie Lumbers
Scheme Research Grant
Role Lead
Funding Start 2008
Funding Finish 2010
GNo G0188642
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

LED fluorescence illuminators and filter set (525nm + 575DF20) for LAS3000 image analysis system$9,600

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Roger Smith, Professor Ian Symonds, Conjoint Associate Professor Andrew Bisits, Conjoint Professor Tamas Zakar, Doctor John Fitter, Doctor Cheng Chan, Conjoint Associate Professor Rick Nicholson, Doctor Giavanna Angeli, Doctor Kaushik Maiti, Doctor Jonathan Paul, Professor Jon Hirst, Doctor Hannah Palliser, Professor Eugenie Lumbers
Scheme Equipment Grant
Role Investigator
Funding Start 2008
Funding Finish 2008
GNo G0188543
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20071 grants / $20,000

Regulation of prostaglandin synthesis by the prorenin/renin system in preterm labour$20,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Professor Eugenie Lumbers, Conjoint Professor Tamas Zakar
Scheme Project Grant
Role Lead
Funding Start 2007
Funding Finish 2007
GNo G0187244
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y
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Research Supervision

Number of supervisions

Completed2
Current5

Total current UON EFTSL

PhD1.35

Current Supervision

Commenced Level of Study Research Title Program Supervisor Type
2017 PhD The Role of the Prorenin/(Pro)Renin Receptor Pathway in Placentation; Implications for Pregnancies Complicated by Preeclampsia PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2016 PhD The Role of Prorenin and the Prorenin Receptor in Successful Placentation PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2016 PhD The Role of miRNAs in Placental Development and Function: Implications for Pregnancies Complicated by Placental Insufficiency PhD(Experimental Pharmacology), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD The Role of Intrauterine Tissue Renin-Angiotensin Systems in Pregnancy and Reproductive Health PhD (Human Physiology), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2014 PhD The Renin Angiotensin System in Endometrial Cancer PhD (Human Physiology), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor

Past Supervision

Year Level of Study Research Title Program Supervisor Type
2014 PhD The Circulating, Intrauterine and Intrarenal Renin Angiotensin Systems in Normal and Pathological Pregnancies PhD (Human Physiology), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2013 PhD Regulation of the Uteroplacental Renin-Angiotensin System in Human Pregnancy PhD (Human Physiology), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
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Professor Eugenie Lumbers

Position

Professor
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Focus area

Pharmacy and Experimental Pharmacology

Contact Details

Email eugenie.lumbers@newcastle.edu.au
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