The prorenin-renin-angiotensin-aldosterone system (RAAS) will be investigated in normal and hypertensive pregnancy. To evaluate the role of angiotensin II in the hemo-dynamic changes of pregnancy, the effect of converting enzyme inhibition (CEI) will be studied in women with scheduled abortions; blood pressure, renin, glomerular filtration rate (GFR), renal plasma flow (RPF), urine sodium excretion and uteroplacental flow velocity profiles will be measured. To relate hemodynamic changes to RAAS in pregnancy, longitudinal studies of normals, pregnancy-induced hypertensives and chronic hypertensives (30% develop superimposed preeclampsia) will be carried out; GFR and RPF or uterine blood flow (vaginal Doppler ultrasound) will be measured. To define first trimester changes, in vitro fertilization and ovarian failure patients, who have a broad spectrum of plasma prorenins will be studied. Since interrelated changes in renin and prostaglandins may participate in pathogenesis of hypertensive pregnancy, RAAS, prostaglandins and uteroplacental flow velocity profiles will be monitored during a placebo controlled trail of low dose aspirin in chronic hypertensives. In parallel invasive studies, microsphere measurements of the distribution of cardiac output to the reproductive and non- reproductive organs and bloods volume measurements will be made in unrestrained, awake pregnant cynomolgus monkeys. In them the effects of both acute and chronic blockade of the RAAS will CEI will also be monitored. During years 4 and 5 hypertensive monkeys will be bred and similarly studied. The function of placental prorenin will be investigated in vitro. The effects of the renin system on steroid biosynthesis and of steroids and gonadotropins on prorenin biosynthesis and secretion will be evaluated using tissue culture, cell superfusion and cotyledon perfusion techniques. Ligand binding studies will be performed to identify and characterize prorenin receptors. The transfer of prorenin between maternal and fetal circulations will be investigated. This application is from an internist/nephrologist, an obstetrician and a basic scientist who have on ongoing and interdependent relationship because of their common interest in hypertension of pregnancy. Together their studies should help to clarify the role of the prorenin-renin-angiotensin-aldosterone system in the maintenance of cardiovascular homeostasis in normal and hypertensive pregnancy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040152-02
Application #
3357267
Study Section
(SRC)
Project Start
1987-09-30
Project End
1992-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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Itskovitz-Eldor, J; Kol, S; Lewit, N et al. (1997) Ovarian origin of plasma and peritoneal fluid prorenin in early pregnancy and in patients with ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 82:461-4
August, P; Mueller, F B; Sealey, J E et al. (1995) Role of renin-angiotensin system in blood pressure regulation in pregnancy. Lancet 345:896-7
Sealey, J E; Itskovitz-Eldor, J; Rubattu, S et al. (1994) Estradiol- and progesterone-related increases in the renin-aldosterone system: studies during ovarian stimulation and early pregnancy. J Clin Endocrinol Metab 79:258-64
Weiner, Z; Thaler, I; Levron, J et al. (1993) Assessment of ovarian and uterine blood flow by transvaginal color Doppler in ovarian-stimulated women: correlation with the number of follicles and steroid hormone levels. Fertil Steril 59:743-9
Pitarresi, T M; Rubattu, S; Heinrikson, R et al. (1992) Reversible cryoactivation of recombinant human prorenin. J Biol Chem 267:11753-9
Itskovitz, J; Bruneval, P; Soubrier, F et al. (1992) Localization of renin gene expression to monkey ovarian theca cells by in situ hybridization. J Clin Endocrinol Metab 75:1374-80
Thaler, I; Weiner, Z; Itskovitz, J (1992) Systolic or diastolic notch in uterine artery blood flow velocity waveforms in hypertensive pregnant patients: relationship to outcome. Obstet Gynecol 80:277-82
Thaler, I; Weiner, Z; Itskovitz, J (1992) Renal artery flow velocity waveforms in normal and hypertensive pregnant women. Am J Hypertens 5:402-5
Gahnem, F; Sealey, J E; Atlas, S A et al. (1992) Inhibition of human renin by rat plasma. Rat angiotensinogen is a competitive inhibitor of the human renin-substrate interaction. Am J Hypertens 5:495-501

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