Ischemic myocardial cell injury. Prevention by chlorpromazine of an accelerated phospholipid degradation and associated membrane dysfunction

Abstract

Ligation of the left coronary artery of an adult rat heart results in the reproducible ischemic cell death of the entire free wall of the left ventricular myocardium. The time course of the development of the cellular changes is biphasic. The subendocardial and subepicardial cells die within the first few hours. The main mass of free-wall myocardium reacts more slowly, with morphologic evidence of irreversible cell injury developing after 12 hours. Measurement of the increases in total free wall Ca++ reflected this biphasic pattern. There was a rapid 3-fold rise in total Ca++ during the first 4 hours. Between 4 and 12 hours the Ca++ was constant. Between 12 and 30 hours there was a second increase that reached a level some 8-10 times the control value. Treatment with chlorpromazine before and subsequent to surgery prevented the appearance of ischemic cell death in the main portion of the free-wall myocardium for at least 24 hours without affecting the reaction of the subepicardial and subendocardial cells. Chlorpromazine also inhibited the second phase of Ca++ accumulation. An accelerated degradation of phospholipids was observed with a 33% decrease in total phospholipids by 12 hours. Phosphatidylethanolamine was reduced by 50% and phosphatidylcholine by 25% without increases in the corresponding lysophospholipids. Chlorpromazine prevented the accelerated degradation and consequent loss of phospholipid. Isolated sarcoplasmic reticulum showed a time-dependent loss of phospholipid with a parallel loss of active Ca++ uptake that reach 60% with a total lipid depletion from these membranes of 33% by 12 hours. Twelve-hour ischemic sarcoplasmic reticulum exhibited a 6--7-fold increase in passive permeability to Ca++. Chlorpromazine protected against the loss of phospholipids, the inhibition of Ca++ uptake, and the increased Ca++ permeability of the sarcoplasmic reticulum. These observations indicate that rat myocardial cells react to lethal doses of ischemia in a manner similar to the reaction of liver cells described previously. In both cases the evidence implies that a disturbance in phospholipid metabolism and its associated membrane dysfunction is the critical alteration that produces irreversible cell injury in ischemia.