Tilting the balance between vasopressors and vasodepressors may result in either a significant hypertensive or antihypertensive effect. The general hypothesis to be tested is that kinins acting as paracrine hormones are an important component of the vasodepressor side of this equilibrium, regulating blood pressure both by decreasing vascular resistance and by acting as renal natriuretic hormones.
In specific aim I, we will test the hypothesis that kinins acting as paracrine hormones play a role in the long-term regulation of cardiovascular and renal function and that decreases in kinin activity facilitate the development of hypertension. We propose to study the effect of chronic blockade of kinins in experimental situations which lead to the development of hypertension and in models of low-renin hypertension, using a novel kinin receptor antagonist with more potency than those used previously.
In specific aim II we will test the effect of chronic blockade of kinins on the cardiovascular and renal actions of kininase II or angiotensin I-converting enzyme (ACE) inhibitors in various models of hypertension and heart failure in the rat. We hypothesize that ACE inhibitors tilt the balance toward antihypertensive activity, not only because they block angiotensin II formation but also because they inhibit cleavage of paracrine kinins.
In specific aim III, we will study the effect of chronic blockade of kinins on the cardiovascular, diuretic and natriuretic actions of an inhibitor of a different kininase, metalloendopeptidase-24.11 (MEP-24.11). These studies will be performed using models of low-renin hypertension and heart failure. We hypothesize that the effects of MEP-24.11 inhibitors are mediated by both ANF and kinins. Kinins appear to play an important role in the acute and pronounced hypotensive effect of an inhibitor of another kininase, metalloendopeptidase 24-15 (MEP-24.15).
In specific aim I V we propose to determine whether MEP-24.15 inhibitors have a chronic antihypertensive effect on various models of hypertension, and whether this effect is mediated by kinins and/or ANF. The studies proposed are of importance since they will improve our understanding of the role of kinins in the long-term regulation of cardiovascular and renal function and the mechanism(s) mediating the chronic effects of ACE, MEP-24.11 and MEP-24.15 inhibitors.
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