Portal hypertension is one of the more serious clinical complications of advanced liver disease. Current therapy of portal hypertension is limited by our poor understanding of the basic mechanisms involved in its development and maintenance. Recent work has identified a 2-3 fold increase in portal venous inflow (forward flow theory) as an important factor in the maintenance of portal hypertension. Evidence now supports the idea that prostacyclin (PGI2) or glucagon (potent splanchnic vasodilators) may be involved in the increase flow phenomenon. This project proposes to determine whether the actions of PGI2 or glucagon are central to the development and maintenance of portal hypertension, if PGI2 or glucagon mediate or modulate the action of the autonomic nervous control of splanchnic hemodynamics, and finally, if the increase in portal hypertension of PGI2 and glucagon are related and quantitate their relative effects on portal blood flow. Part I will study whether PGI2 mediates or modulates the portal hemodynamic effects of the autonomic nervous system by utilizing selective blockade and stimulation of various limbs of the autonomic nervous system in the portal hypertensive and normal rabbit model. Part II will test the hypothesis that PGI2 may be related to the action of glucagon. Whether the elevations of PGI2 and glucagon are related via the autonomic nervous system will also be determined. Glucagon administration in rabbits with and without cyclo- oxygenase blockade as well as autonomic blockade/stimulation will be performed, and the effect on PGI2 production and splanchnic hemodynamics measured. Part III will attempt to determine the stimulus for the rise of PGI2, glucagon, and mesenteric flow observed in portal hypertensive animals by performing selective splanchnic vein ligation, portosystemic shunt, hepatic arterial ligation, and cirrhosis induced, and the effect on mesenteric, hepatic, and portal flow, pressure and resistance, and PGI2 and glucagon production, organ oxygen differences will be measured to determine the regulated variable causing portal hypertension. Part IV will attempt to confirm the role of PGI2/glucagon in portal hypertensive humans. Systemic and portal PGI2/glucagon and splanchnic blood flow will be measured. The effect of normalization of portal pressure (portosystemic shunt) on the hyperemia of human portal hypertension will be studied. The results of these studies will provide information about the pathophysiology of portal hypertension and indicate the hormonal/pharmacologic/anatomic manipulations which would favorably alter the sequelae of portal hypertension.
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