Abstract

We propose to test the following hypothesis: 1) local release of endothelium derived nitric oxide (EDNO) plays a significant role in the increase in myometrial and endometrial blood flow observed during pregnancy.
The Specific Aim to test this part of the hypothesis would be to demonstrate the effects of selected inhibitors of EDNO synthesis in selectively decreasing uterine blood flow in pregnant rats at various stages of gestation using the hydrogen clearance technique. 2) This increase in gestation related release and action of EDNO in individual arterioles is more prominent for the uterine vascular bed (as compared to another visceral vascular bed).
The Specific Aim to test this part of the hypothesis would be, to demonstrate the developmental changes during gestation in basal and stimulated release and action of EDNO as well as the cyclic GMP mediated vasodilatory system of mesometrial arterioles of pregnant rats in vivo when compared to gastric submucosa arterioles using the in vivo microscopy technique; 3) The increase in ENDO release and action in the uterine vascular bed during pregnancy is modulated by sex steroids.
The Specific Aim to test this part of the hypothesis would be to demonstrate the modulating role of estradiol (E2) and progesterone (P) on the release and action of EDNO from the uterine vascular bed and the cellular mechanism of such action. Long Term Objectives The generation and actions of EDNO in increasing uterine blood flow (UBF) and diminishing uterine vascular resistance will have important basic and clinical implications. The results of these studies may indicate the regulatory raechanism by which EDNO release and action is increased during pregnancy and how sex steroids modulate this effect. The results would lay the foundation for future studies to assess the role of EDNO in the pathophysiology of certain diseased states associated with pregnancy, such as hypertension and diabetes, conditions where the fetus may be adversely affected.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL046843-01
Application #
3366014
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1991-08-01
Project End
1994-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Shah, S; Nathan, L; Singh, R et al. (2001) E2 and not P4 increases NO release from NANC nerves of the gastrointestinal tract: implications in pregnancy. Am J Physiol Regul Integr Comp Physiol 280:R1546-54
Nathan, L; Shi, W; Dinh, H et al. (2001) Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase. Proc Natl Acad Sci U S A 98:3589-93
Singh, R; Pervin, S; Karimi, A et al. (2000) Arginase activity in human breast cancer cell lines: N(omega)-hydroxy-L-arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res 60:3305-12
Singh, R; Pervin, S; Shryne, J et al. (2000) Castration increases and androgens decrease nitric oxide synthase activity in the brain: physiologic implications. Proc Natl Acad Sci U S A 97:3672-7
Shah, S; Hobbs, A; Singh, R et al. (2000) Gastrointestinal motility during pregnancy: role of nitrergic component of NANC nerves. Am J Physiol Regul Integr Comp Physiol 279:R1478-85
Nathan, L; Pervin, S; Singh, R et al. (1999) Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo : possible mechanisms for gender differences in atherosclerosis. Circ Res 85:377-85
Grewal, M; Cuevas, J; Chaudhuri, G et al. (1999) Effects of calcitonin gene-related peptide on vascular resistance in rats: role of sex steroids. Am J Physiol 276:H2063-8
Hyun, J; Chaudhuri, G; Fukuto, J M (1999) The reductive metabolism of nitric oxide in hepatocytes: possible interaction with thiols. Drug Metab Dispos 27:1005-9
Pervin, S; Singh, R; Rosenfeld, M E et al. (1998) Estradiol suppresses MCP-1 expression In vivo : implications for atherosclerosis. Arterioscler Thromb Vasc Biol 18:1575-82
Nathan, L; Chaudhuri, G (1997) Estrogens and atherosclerosis. Annu Rev Pharmacol Toxicol 37:477-515

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