The studies proposed are to further our knowledge of the role of the vascular renin-angiotensin system. A major objective is to provide a better understanding of the contribution of local angiotensin II (AII) - induced renal vascular tone in the normal and hypertensive state, and whether blockade of this tone by ACE and renin inhibitors contributes to their antihypertensive action.
Four specific aims derived from recent investigations from this laboratory will be pursued.
Specific aim 1 is based on the finding that beta-adrenoceptor stimulated release of renin from the kidney leads to the production of locally formed AII in the femoral vascular bed. Experiments conducted in anesthetized rabbits in which blood pressure and femoral blood flow are measured will involve acute and 24 hr i.a. infusion of rabbit renin into the femoral vascular bed to see if exogenous renin from the circulating blood and/or taken up by the vessels is utilized for locally produced AII. also, whether the circulating or bound renin leads to AII formation and potentiation of adrenergic responses in the femoral bed is another objective of these experiments. As a second specific aim, the effects of threshold doses of captopril and renin inhibitor, EMD 58265 on renal hemodynamics and function will be determined. The hypothesis is that endothelial- or smooth muscle-generated AII is inhibited by these threshold doses resulting in decreased renal vascular tone without affecting AII- regulated tubular function. Relative changes in papillary and cortical blood flow will be measured in these experiments. Effects of threshold doses of these agents will also be ascertained in one kidney 1-clip Goldblatt hypertensive rabbits.
Specific aim 3 is to delineate the regulatory factors affecting renin and AII release, i.e., beta- adrenoceptor agonist; endoperoxide-mimetic, U46619, PGE2; perfusion pressure and nitric oxide, in the rabbit Krebs-perfused intrarenal arterial network (IAN). Measurement of AII in the perfusate from the IAN will be by radioimmunoassay after HPLC separation. Renin activity will be determined by AI generation of incubated extracts of the perfusate.
Specific aim 4 is to extend studies on the mechanism of the long term action of ACE inhibitors. AII content of the IAN and ACE activity in the rabbit kidney will be contrasted after acute and 6-day lisinopril treatment. It is hypothesized that greater blood pressure, renal hemodynamic and adrenergic suppressant effects of long term ACE inhibition is due to greater decrease in renally generated AII. This research is intended to define the role that locally formed AII plays in the renal and femoral vascular beds, and whether vascular endothelium and/or smooth muscle are the sources of AII that regulate vascular tone. These considerations may be important in relation to the involvement of locally formed AII in hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039698-09
Application #
2028353
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1988-03-01
Project End
1997-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zimmerman, B G (2000) Greater blood pressure-lowering effect of the renin inhibitor EMD 58265 than an angiotensin-converting enzyme inhibitor in two-kidney one-clip Goldblatt rabbit. Clin Exp Pharmacol Physiol 27:370-7
Zimmerman, B G; Birt, P C (1997) Angiotensin II release from rabbit intrarenal arteries: a critical assessment. Am J Hypertens 10:306-14
Chen, K; Zhang, X; Dunham, E W et al. (1996) Kinin-mediated antihypertensive effect of captopril in deoxycorticosterone acetate-salt hypertension. Hypertension 27:85-9
Chen, K; Zimmerman, B G (1995) Angiotensin II-mediated renal vasoconstriction amenable to alpha 1-adrenoceptor blockade. Eur J Pharmacol 284:281-8
Zhang, X; Dunham, E W; Zimmerman, B G (1995) Threshold sodium excretory and renal blood flow effects of angiotensin converting enzyme inhibition. J Hypertens 13:1413-19
Birt, P C; Zimmerman, B G (1995) Intrarenal arterial network renin content and inhibition by EMD 58265. Am J Hypertens 8:433-6
Chen, K; Zimmerman, B G (1994) Comparison of renal hemodynamic effect of ramiprilat to captopril;possible role of kinins. J Pharmacol Exp Ther 270:491-7
Zimmerman, B G; Raich, P C (1992) Renal hemodynamics in canine DOCA-salt hypertension: effect of calcium channel blockade. Tohoku J Exp Med 166:147-54
Hajj-Ali, A F; Zimmerman, B G (1992) Enhanced blood pressure and renal hemodynamic effect of chronic versus acute lisinopril administration in the rabbit. J Pharmacol Exp Ther 263:158-62
Hajj-ali, A F; Zimmerman, B G (1992) Nitric oxide participation in renal hemodynamic effect of angiotensin converting enzyme inhibitor lisinopril. Eur J Pharmacol 212:279-81

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