The long-term goals of the proposed research are to understand both the intrinsic factors which normally regulate the circulation of the gut and the intrinsic mechanisms whereby vasodilator agents increase mesenteric blood flow. There will be two specific aims: 1) to test the hypothesis that a physiological phenomenon, autoregulation of intestinal blood flow, is mediated by an intrinsic substance, histamine; and 2) to determine whether calcium entry blockers which vasodilate the intestinal circulation act only at sarcolemmal sites on mesenteric vascular smooth muscle or also act intracellularly. The clinical significance of this research relates to non-occlusive intestinal ischemia, an acute and usually lethal state of intestinal vasospasm whose cause is unknown and whose treatment is unsatisfactory. The hypothesis that histamine is the chemical transducer of autoregulation in the gut will be tested by evoking three intrinsic autoregulatory events, namely pressure autoregulation of blood flow, reactive hyperemia and autoregulatory escape, and then attempting to block these events with histamine H-1 and H-2 receptor antagonists, as well as agents which interfere with histamine metabolism. Several hemodynamic and metabolic parameters will be used in anesthetized and conscious canine preparations to assess the effects of histamine receptor antagonists and enzyme inhibitors, namely mesenteric blood flow, arterial and venous pressures, intestinal oxygen extraction and consumption, autoregulatory indices and mesenteric vascular resistance. The study of vasodilator mechanisms with calcium entry blockers will utilize similar techniques as well as in vitro preparations, namely excised mesenteric arterial strips mounted in a muscle bath and the binding of radiolabeled calcium entry blockers to sarcolemmal membrane preparations.
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