The aim of this proposal is to a) quantitate the importance of intrahepatic shunting vs that of capillarization of sinusoids to explain functional alterations in cirrhosis of the liver, b) to differentiate between the """"""""intact cell"""""""" and """"""""the sick cell"""""""" hypothesis of liver disease by quantitating the intrinsic clearance of a variety of endogeneous and exogenous compounds c) and to investigate possible means of pharmacologically alleviating portal hypertension. The studies will be performed in rats rendered cirrhotic by chronic exposure to phenobarbital and carbon tetracholoride. A novel liver perfusion system allowing perfusion of both, the portal venous and the hepatic arterial bed, will be employed. Intrahepatic shunting in both these vascular beds will be quantitated by a microsphere technique. Capillarization of the sinusoids will be investigated by a multiple indicator dilution technique using labeled erythrocytes as intravascular, sucrose and albumin as extravascular and tritiated water as intracellular indicators. Appropriate modeling of the hepatic circulation will permit differentiation between flow-limited distribution (as seen in normal liver) and barrier-limited distribution (as seen in capillarized organs such as the myocardium) of the extravascular indicators. Hepatocellular function will be measured by determining the kinetic parameters of the uptake of tauro-cholate and bilirubin, endogeneous compounds with high and low extraction, respectively. The uptake of both is dependent upon carrier-mediated membrane transport. As a further measure of intrinsic clearance, the kinetic behaviour of propranolol and antipyrine, exogeneous model compounds with high and low extraction, will be studied in the intact animal, the perfused liver and suspensions of isolated hepatocytes. Both compounds enter the hepatocyte passively and undergo extensive microsomal metabolism. Their metabolic fate will be investigated by studying their biotransformation in the perfused liver, isolated hepatocytes and microsomal fractions. These studies, taken together, will give an appreciation of the quantitative importance of microcirculatory changes vs that of a loss of hepatocellular mass. Finally, the potential of propranolol, verapamil and glycerol trinitrate to lower portal hypertension will be investigated. If successful, the influence of these drugs on hepacellular function and microcirculation will be investigated by the methods outlined above.
