Portal hypertension, a clinical problem that often arises as a result of cirrhosis or other forms of liver disease, is characterized by an elevated portal pressure, portosystemic shunting and a hyperdynamic circulatory state. One of the hallmarks of the hyperdynamic circulation is an intense intestinal vasodilation that appears to be due to elevations in circulating vasodilators and reductions in vasoconstrictor sensitivity. Many investigators believe that the hyperdynamic intestinal circulation is a key factor which maintains the portal hypertensive condition. As such, pharmacological therapy of portal hypertension often involves the use of drugs that decrease portal pressure by decreasing intestinal blood flow. The purpose of the proposed studies is to systematically analyze the intestinal microvascular adaptation to portal hypertension in order to test the hypothesis that intestinal microvessels dilate as a result of a reduced responsiveness to exogenous and endogenous vasoconstrictor stimuli. For these studies, the intestine of normal and portal hypertensive rats is viewed through a video-microscope and arterioles in the mucosa, submucosa or muscularis studied. Arteriolar diameter, erythrocyte velocity, intravascular pressure and blood flow are measured in sequentially branching arterioles. Tension generation by individual arterioles can be calculated from the pressure and diameter data.
The specific aims are: 1) To determine the site of altered vasoconstrictor sensitivity in the portal hypertensive intestinal microcirculation (The responsiveness of intestinal arterioles to norepinephrine, vasopressin and angiotensin II will be studied in normal and portal hypertensive rats to determine if reductions in intestinal vascular sensitivity are restricted to specific loci in the microcirculation); 2) To determine the contribution of neurohumoral vasoconstrictor systems to resting intestinal vascular tone in normal and portal hypertensive rats (The contribution of the sympathetic nervous system, arginine vasopressin and the renin-angiotensin system to intestinal arteriolar tone will be determined by selectively removing the influences of these systems with specific antagonists); 3) To determine if reductions in the intrinsic myogenic reactivity of intestinal arterioles contribute to the lower vascular tone in chronic portal hypertension (These studies will analyze the myogenic responsiveness of intestinal arterioles of portal hypertensive rats to step increments in transmural pressure. Studies will also be conducted in portacaval shunted rats to determine if changes in the myogenic reactivity of intestinal arterioles are consequence of the hyperdynamic circulation or an adaptation to a chronically elevated portal pressure); 4) To determine if the reduced responsiveness of intestinal arterioles to extrinsic and intrinsic vasoconstrictor stimuli are related to high plasma levels of glucagon and bile acids in portal hypertension (Plasma glucagon or bile acid levels will be depleted by immuno- neutralization or bile fistula and the responsiveness of intestinal arterioles to vasoconstrictor stimuli evaluated. These studies will allow us to determine if decreased vasoconstrictor sensitivity is a response to portal hypertension or a result of elevated vasodilator mediators of the hyperdynamic circulation. The results of the proposed studies will provide new information regarding the hyperdynamic intestinal circulation and will prove useful in developing new modes of therapy of portal hypertension.
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