PROTECTIVE EFFECTS OF THE CALCIUM-CHANNEL BLOCKER VERAPAMIL ON HEPATIC-FUNCTION FOLLOWING WARM ISCHEMIA

The purpose of this study was to investigate the protective effects of the calcium channel blocker verapamil on warm ischemia-reperfusion in jury to the liver using a rat model. Ischemia of the left and median l obes was created by total inflow occlusion for 60 min followed by 24 h r of reperfusion. Hepatocell injury was assessed by the release of liv er enzymes [alanine aminotransferase (ALT) and lactic dehydrogenase (L DH)], reduced (GSH) and oxygenated (GSSG) plasma glutathione and total biliary glutathione. Hepatocyte function was quantitated by measuring bile how. Rats were randomized to one of two groups: pretreatment wit h iv verapamil (0.3 mg/kg) or iv normal saline (controls). Verapamil s ignificantly increased bile flow and biliary GSH efflux while decreasi ng plasma ALT and LDH compared to those in controls 24 hr after liver ischemia-reperfusion (LIR). A significant correlation existed between bile flow and biliary GSH efflux at 1 but not 24 hr after LIR, suggest ing that early LIR injury is mediated predominantly by generation of o xygen free radicals. Liver enzyme elevation and bile flow were inverse ly correlated at 24 but not 1 hr after injury. We conclude that verapa mil significantly protects the liver against warm LIR injury. The mini mal protective effect of verapamil on early liver ischemia-reperfusion demonstrates that verapamil does not prevent the early generation of oxygen radicals upon reperfusion. However, the significant restoration of biliary GSH efflux and hepatocyte protection at 24 hr suggests inv olvement of calcium ions in late hepatocyte injury. Verapamil's protec tive effects may be related to attenuating pathophysiologic events occ urring beyond 1 hr of reperfusion. Future studies investigating the pr otective effects of verapamil on warm LIR injury should be carried out for at least 24 hr postreperfusion. (C) 1996 Academic Press, Inc.