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 as a reduction in oxygen-dependent enzyme activity including phase 1 drug metabolism. The hepatic artery supplies highly oxygenated blood to the liver. Therefore, we tested whether augmentation of hepatic arterial blood flow could improve hepatic oxygenation and function in cirrhosis. Rats were treated 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 oxygen 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 propranolol 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 was mediated by change in oxygen delivery alone (P =.001). The results confirm that propranolol metabolizing enzyme activity in cirrhosis can be improved 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 cirrhosis.
Le Couteur
D G
DG
Canberra Clinical School of the Sydney University, The Canberra Hospital, Canberra, Australia.
Hickey
H
H
Harvey
P J
PJ
Gready
J
J
McLean
A J
AJ
D000818:Animals; D001835:Body Weight; D006499:Hepatic Artery / Q000502:physiology* / Q000503:physiopathology; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008102:Liver Circulation; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D009929:Organ Size; D010101:Oxygen Consumption; D010477:Perfusion; D011169:Portal Vein / Q000502:physiology / Q000503:physiopathology; D011433:Propranolol / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D014655:Vascular Resistance
D011433:Propranolol