This proposal is aimed at exploring the mechanisms underlying the hyperdynamic circulation in rats with cirrhosis and portal hypertension. Portal hypertension results from increased vascular resistance in the portal bed, a condition that leads to portasystemic shunting. The PI proposes that vasodilator substances, particularly glucagon, are shunted around the liver and contribute to arteriolar vasodilation and increased systemic blood flow, hallmarks of the cirrhotic hyperdynamic circulation. A second major mechanism in this pathophysiologic response is that small arterioles appear to be less sensitive to vasoconstrictor substances such as norepinephrine. These two mechanisms, increased circulating vasodilators and diminished response to vasoconstrictors, would be additive in causing or contributing to the vascular abnormalities of portal hypertension. The experimental model to be used in these studies will be an in vitro preparation of small mesenteric arteries (150-200 um diameter) taken from control rats or rats made cirrhotic with carbon tetrachloride. The vessel rings will be mounted in a myograph to measure contraction. The same vessel preparation will be loaded with a calcium sensitive flo (Flo 3 AM) to permit measurement of intracellular calcium. Using this experimental model, the PI proposes to test five major hypotheses: 1) portal hypertension depresses receptor and non receptor-mediated increases in intracellular calcium (Cai) and tension in small resistance arteries; 2) portal hypertension alters the rate of release and sequestration of calcium in vascular smooth muscle. Calcium movement across the plasma membrane and across the sarcoplasmic reticulum using agonists and antagonists will be studied; 3) will investigate whether glucagon interferes with the vasoconstrictor effect of non-epinephrine on vascular smooth muscle, and whether this effect is mediated by cAMP-dependent mechanisms; 4) will examine whether inhibition of adenylyl cyclase or protein kinase A restores the vascular responses to norepinephrine or vasopressin; 5) will examine whether release of NO from vascular endothelium augments cAMP-dependent vasodilator events in resistance arteries from portal hypertensive rats.
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