The purpose of this application is to continue studies on the role of each of the two bradykinin receptors, B1R and B2R, in cardiovascular diseases. We found that mice lacking the B2R gene exhibit induction of the remaining B1R gene, which under normal conditions is unexpressed but inducible by inflammatory mediators. Furthermore, the B1R appears to become upregulated by maneuvers that produce experimental hypertension and to assume some of the hemodynamic functions attributable hitherto to the B2R. The proposed studies will further explore the potential hemodynamic role of each receptor subtype. Our hypothesis is that upregulation of the B1R contributes to bradykinin-mediated protection from hypertensive/ischemic tissue injury provoked by various manipulations that disturb cardiovascular homeostasis.
The Specific Aims are: 1) To investigate the vasodilatory antihypertensive capacity of the B1R by: a) comparing infusions of B1R agonist and antagonist in experimental reninlangiotensin-dependent or sodium-dependent hypertension in B2R gene knockout vs. wildtype mice and b) exploring the cardiovascular phenotype of B1R gene knockout mice when submitted to experimental reninlangiotensin-dependent or sodium-dependent hypertension, 2) To study the cardiovascular phenotype of the double B1 R and B2R gene knockout mouse when submitted to experimental renin/angiotensin-dependent or sodium-dependent hypertension, 3) To assess the relative contributions of the B1R and B2R to the cardioprotective effect of bradykinin after coronary artery ligation to induce myocardial necrosis, by comparing the extent of tissue damage with or without treatment with ACE inhibition in wildtype, B2R gene knockout, B1R gene knockout and double (B1R and B2R) gene knockout mice, 4) To investigate the direct effect of vasoactive substances in vitro in inducing or inhibiting B1R and B2R expression on cultured vascular smooth muscle cells. Understanding the contribution of each bradykinin receptor to vascular responses may help devise means to enhance their tissue-protective properties.
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