PREVENTION BY CHLORPROMAZINE OF ISCHEMIC LIVER-CELL DEATH

Abstract

Ischemic liver tissue was produced by clamping the portal venous and hepatic arterial blood supply to the left lateral and median lobes of rat liver. If, after 2-3 h of ischemia, reflow to the liver was established by removing the clamp, 2/3 or more of the liver cells were histologically dead 24 h later. Pretreatment with chlorpromazine, (20 mg/kg) 30 min before inducing ischemia for up to 3 h, virtually completely prevented this ischemic cell death. If the animals were kept alive for an additional 24 h with no further treatment the extent of liver cell necrosis at 48 h was still markedly less than that seen in the untreated ischemic controls. Administration of chlorpromazine after induction of ischemia and immediately prior to the onset of reflow reduced but did not completely prevent ischemic cell death as determined at 24 h. This protective action of chlorpromazine was confirmed by the ability of the treated animals to regenerate cellular ATP levels after 3 h of ischemia. Chlorpromazine was shown to significantly reduce the increases in total liver cell and mitochondrial Ca2+ contents that accompany the return of blood flow to irreversibly injured liver cells. The protective effect of chlorpromazine could not be attributed to any effect either on the rate or extent to which the liver cells became ischemic or on the perfusion patterns following release of the obstruction. The action of chlorpromazine is probably on some component(s) of the reaction of the cells to the ischemia itself. The possible basis of this action is discussed.