The role of the kallikrein-kinin system and its interaction with the renin-angiotensin system in the kidney and its contribution to the effect of angiotensin converting enzyme (ACE) inhibitors is not well understood. Through the use of agents that block the kallikrein-kinin system together with angiotensin II (All) antagonists, we will determine the influence of kinins on blood pressure (BP), renal blood flow (RBF), GFR, urine flow, and sodium and potassium excretion in the anesthetized rabbit. These parameters will be measured under basal conditions and during inhibition of ACE. Kinin influence will be contrasted under conditions of sodium restriction, sodium supplementation and in three forms of hypertension. Both the acute and chronic application of ACE inhibitors will be examined under these various conditions. It is hypothesized that there is an interaction between the renin-angiotensin system and the kallikrein-kinin system. By analyzing the vascular participation of kinins and AH when these systems are activated, we will gain information about BP and blood flow regulation by these peptide hormones. BP and RBF, by electroflowmetry, will be monitored, plasma renin activity determined, and the effects of bradykinin antagonist, DArg(Hyp3,DPhe7) bradykinin (NPY 567) and new nonpeptide All antagonist (DUP 753) or saralasin determined on BP, RBF, renal function and the response to an ACE inhibitor. After establishing the role of kinins on these parameters In Vivo, more detailed studies on the factors regulating renal kinin release and metabolism will be pursued. A novel preparation of the rabbit intrarenal arterial network developed in this laboratory will be utilized. First, active kallikrein and prekallikrein will be determined in a microsomal fraction of intrarenal arteries from sodium restricted and supplemented animals, and from low and high renin hypertensives. Secondly, the arterial network will be perfused and superfused to allow determination of kinin release from the vascular lumenal and ablumen sites. How AII antagonists, ACE inhibitor, beta-adrenoceptor agonist and antagonist, and inhibitors of kinin metabolism affect kinin release from the renal arteries will provide a better understanding of the kinin role in the normal kidney and that affected by hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044370-03
Application #
2221446
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1991-02-01
Project End
1995-01-31
Budget Start
1993-02-01
Budget End
1995-01-31
Support Year
3
Fiscal Year
1993
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