Our long-term research goal is to elucidate the physiological role of histamine in the regulation of renal hemodynamics and renal function. In this proposal we describe experiments designed to test the hypothesis that 1) histamine is a key modulator of renal blood flow autoregulation, 2) histamine-induced changes in renal hemodynamics and renal function are regulated by several enzymatic steps in the metabolic pathway of histamine, 3) histamine, in part, accounts for the renal vasodilation associated with exogenously administered and endogenously released prostaglandins and 4) histamine-induced renal vasodilation is an endothelial cell dependent event. Our experiments will be performed in pentobarbital anesthetized dogs. Renal blood flow will be measured with an electromagnetic flow probe and all drugs will be administered directly into the renal artery. Experiments designed to address a) hypothesis #1 will focus on determining if decreases in renal arterial pressure cause increases in the renal cortical concentration of histamine, b) hypothesis #2 will focus on evaluating effects of inhibitors of histamine synthesis and metabolism on autoregulatory events and on renal function. In addition, effects of these agents on the renal vasodilation produced by histamine, histamine H1 and H2 receptor agonists and histamine metabolism intermediates, C) hypothesis #3 will be directed towards determining the effects of prostaglandins on renal tissue histamine concentrations. We will also determine the effect of H1 and H2 receptor antagonists and of inhibitors of histamine metabolism on prostaglandin induced renal vasodilation and d) hypothesis #4 will be focused on an evaluation of lipoxygenase inhibitors on histamine-induced renal vasodilation.
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