Diltiazem reduces apoptosis in rat hepatocytes subjected to warm hypoxia-reoxygenation

Abstract

Interruption of hepatic blood flow is necessary in surgery, but the liver is sensitive to ischemia and reperfusion. Hypoxia induces an increase in intracellular calcium concentration. In previous studies, we have shown that hypoxia-reoxygenation (H/R) increased calcium influx and induced JNK(1)/SAPK(1) activation which was involved in the triggering of apoptosis. The aim of this study was to demonstrate that diltiazem, a calcium inhibitor, reduced JNK(1)/SAPK(1) activation and consequently could decrease H/R-induced apoptosis. Experiments were performed, in the presence of diltiazem, on primary cultured rat hepatocytes, subjected to warm H/R phases and in a liver ischemia-reperfusion model. The activation status of JNK(1)/SAPK(1) was evaluated by immunoprecipitation and immunohistolocalisation experiments, while apoptosis was assessed by measuring caspase activity and by TUNEL labeling. Diltiazem inhibited H/R-induced JNK(1)/SAPK(1) activation and decreased apoptosis. It could be used to improve postoperative liver function.