The longterm objectives of this proposal are: 1) to define the regulating mechanisms of hepatic and systemic hemodynamics in liver disease, and determine in which patients pharmacologic manipulation is beneficial to hepatic function: and 2) to initiate study of the hemodynamics of the denervated, transplanted liver. The first objective will be achieved in two phases. Firs, a prospective randomized trial will be conducted in patients with alcoholic cirrhosis after distal splenorenal shunt. This will test the hypothesis that reduction of the systemic hyperdynamic response with propranolol will lower intrahepatic resistance sufficient to allow maintenance of portal flow and hepatic function, with improved survival. In parallel to this study, propranolol, verapamil, ketanserin and the nitrates, drugs which lower intrahepatic resistance, will be evaluated in stable patients with cirrhosis. This phase will test the hypothesis that reduction of intrahepatic resistance will improve portal perfusion and hepatic function. Methodologic studies focus on measurement of portal flow and peripheral vascular resistance. These will use Doppler/ultrasound, magnetic resonance imaging, and angiodynography. Differentiation of peripheral (limb) vascular resistance from total systemic vascular resistance will help elucidate mechanisms of pharmacologic manipulation. The transplanted liver is denervated, and hence the neural control of blood flow is lost. Liver blood flow and portal venous flow will be measured in transplant patients to test the hypothesis that blood flow is increased, and this is primarily through increased hepatic arterial flow. Studies will be conducted in a pig model of liver denervation to define the altered hepatic and systemic hemodynamics, and the response to hypovolemic shock. Cirrhosis has a high morbidity/mortality with variceal bleeding and liver failure. Improved regulation of the abnormal hemodynamics, which are the common denominator to this morbidity, should significantly enhance patient care. The increased application of liver transplant mandates the need for careful study of the pathophysiology of the hemodynamic alterations after transplant and their longterm impact on graft function. These two objectives have common ground in the regulating mechanisms o liver blood flow in health and disease.
