The unifying hypothesis of this project is that the synthesis, metabolism and activity of angiotensin-converting enzyme (ACE) are regulated by a variety of factors, including level of oxygenation of the environment and naturally occurring substrates and synthetic inhibitors of the enzyme, and that the consequent alterations in ACE function influence cardiovascular homeostasis and the pathogenesis of some forms of hypertension by modulating the generation of vasoactive peptides. The major portion of this application is directed toward an examination of the regulation of ACE synthesis and metabolism and of ACE activity in vivo in the pulmonary and systemic circulations of the rat and in vitro in cultured endothelial cells. Specificially, and hypotheses that exposures to chronic normobaric hypoxia and chronic normobaric hyperoxia inhibit ACE synthesis and that naturally occurring substrates of ACE (such as angiotensin I, AI) and ACE inhibitors induce the synthesis of the enzyme will be examined. Specific radioimmunoassays for rat, porcine and human ACE will be developed and used in conjunction with a conventional spectrophotometric assay of enzyme activity and a novel inhibitor binding assay which indentifies the active sites of the ACE molecule. These three assays for ACE will complement one another because antibodies, substrates and inhibitors may recognize different sites on the ACE molecule and a substantial proportion of the ACE molecules synthesized by the intact animal in vivo and endothelial cells in vitro may lack catalytic activity. In addition, radiolabeling techniques will be used to quantitate the synthesis, degradation and release of Ace by cultured endothelial cells. The effects of altered endogeneous ACE on the control of the pulmonary and systemic circulations will be studied in normal animals and in various pathophysiologic states, including hypoxia- induced pulmonary hypertension and two kidney, one clip (2K, 1C) renovacular hypertension in the rat. In the 2K, 1C rat, we will test the hypothesis that ACE content and activity are increased in the nonclipped kidney and that this increase in ACE activity enhances intrarenal angiotensin II (AII) production, thereby contributing to altered renal function and to the pathogenesis of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL022544-13
Application #
3336928
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1987-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1993-03-31
Support Year
13
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Zhu, S T; Chen, Y F; Wyss, J M et al. (1996) Atrial natriuretic peptide blunts arterial baroreflex in spontaneously hypertensive rats. Hypertension 27:297-302
Meng, Q C; Durand, J; Chen, Y F et al. (1993) Simplified method for quantitation of angiotensin peptides in tissue. J Chromatogr 614:19-25
Wyss, J M; Mozaffari, M S; St John, P L et al. (1993) Cyclosporine-induced nephrotoxicity in deoxycorticosterone-NaCl treated rats. Int J Exp Pathol 74:615-26
Lipke, D W; McCarthy, K J; Elton, T S et al. (1993) Coarctation induces alterations in basement membranes in the cardiovascular system. Hypertension 22:743-53
Nakamura, Y; Calhoun, D A; Chen, Y F et al. (1993) Excitatory sympathetic reflex in NaCl-sensitive spontaneously hypertensive rats. Hypertension 22:285-91
Wyss, J M; Oparil, S; Sripairojthikoon, W (1992) Neuronal control of the kidney: contribution to hypertension. Can J Physiol Pharmacol 70:759-70
Contreras, R J; Oparil, S (1992) Sex difference in blood pressure of spontaneously hypertensive rats influenced by perinatal NaCl exposure. Physiol Behav 51:449-55
Jin, H; Mathews, C; Chen, Y F et al. (1992) Effects of acute and chronic blockade of neutral endopeptidase with Sch 34826 on NaCl-sensitive hypertension in spontaneously hypertensive rats. Am J Hypertens 5:210-8
Wyss, J M; Van Groen, T (1992) Early breakdown of dendritic bundles in the retrosplenial granular cortex of hypertensive rats: prevention by antihypertensive therapy. Cereb Cortex 2:468-76
Chen, Y F; Naftilan, A J; Oparil, S (1992) Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension 19:456-63

Showing the most recent 10 out of 91 publications