Hepatic artery flow and propranolol metabolism in perfused cirrhotic rat liver

The oxygen limitation theory states that capillarization of the sinusoidal endothelium in cirrhosis impairs hepatocellular oxygen uptake manifesting a s a reduction in oxygen-dependent enzyme activity including phase 1 drug me tabolism. The hepatic artery supplies highly oxygenated blood to the liver. Therefore, we tested whether augmentation of hepatic arterial blood flow c ould improve hepatic oxygenation and function in cirrhosis. Rats were treat ed with carbon tetrachloride and phenobarbitone to induce hepatic cirrhosis or fibrosis. We used a bivascular rat liver perfusion model to examine the effects of increased hepatic artery flow on propranolol clearance and oxyg en consumption. Each liver was perfused at three hepatic artery flow rates, 1 to 3, 4 to 6, and 7 to 9 ml/min with a constant portal venous flow of 7 to 9 ml/min. Increasing the hepatic artery flow led to improvement in propr anolol clearance in control (n = 7, P < .001), fibrotic (n = 8, P < .001), and cirrhotic (n = 6, P < .001) livers. Intrinsic clearance of propranolol increased only in the cirrhotic livers (P = .01), indicating an improvement in enzyme activity. Regression analysis indicated that this improvement wa s mediated by change in oxygen delivery alone (P = .001). The results confi rm that propranolol metabolizing enzyme activity in cirrhosis can be improv ed by increasing oxygen delivery by increasing hepatic arterial blood flow. These findings suggest that increasing hepatic arterial blood flow may be an important therapeutic strategy for improving global liver function in ci rrhosis.