Le Couteur D G, Hickey H, Harvey P J, Gready J, McLean A J
Canberra Clinical School of the Sydney University, The Canberra Hospital, Canberra, Australia.
J Pharmacol Exp Ther. 1999 Jun;289(3):1553-8.
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.
氧限制理论认为，肝硬化时肝血窦内皮细胞的毛细血管化会损害肝细胞对氧的摄取，表现为包括I相药物代谢在内的氧依赖性酶活性降低。肝动脉为肝脏供应高氧血液。因此，我们测试了增加肝动脉血流量是否能改善肝硬化时的肝脏氧合和功能。用四氯化碳和苯巴比妥处理大鼠以诱导肝硬变或肝纤维化。我们使用双血管大鼠肝脏灌注模型来研究增加肝动脉血流量对普萘洛尔清除率和氧消耗的影响。每个肝脏以三种肝动脉血流速率进行灌注，即1至3、4至6和7至9毫升/分钟，门静脉血流恒定为7至9毫升/分钟。增加肝动脉血流量可使对照（n = 7，P <.001）、纤维化（n = 8，P <.001）和肝硬化（n = 6，P <.001）肝脏的普萘洛尔清除率得到改善。普萘洛尔的内在清除率仅在肝硬化肝脏中增加（P =.01），表明酶活性有所改善。回归分析表明，这种改善仅由氧输送的变化介导（P =.001）。结果证实，通过增加肝动脉血流量来增加氧输送可改善肝硬化时普萘洛尔代谢酶的活性。这些发现表明，增加肝动脉血流量可能是改善肝硬化整体肝功能的一项重要治疗策略。
