ISCHEMIC MYOCARDIAL-CELL INJURY - PREVENTION BY CHLORPROMAZINE OF AN ACCELERATED PHOSPHOLIPID DEGRADATION AND ASSOCIATED MEMBRANE DYSFUNCTION

  • 1 January 1979
    • journal article
    • research article
    • Vol. 97  (3) , 505-530
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 in biphasic. The subendocardial and subepicardial cells die within the first few h. The main mass of free-wall myocardium reacts more slowly, with morphologic evidence of irreversible cell injury developing after 12 h. Measurement of the increases in total free wall Ca2+ reflected this biphasic pattern. There was a rapid 3-fold rise in the total Ca2+ during the first 4 h. Between 4 and 12 h, the Ca2+ was constant. Between 12 and 30 h, there was a 2nd increase that reached a level some 8-10 times the control value. Treatment with chlorpromazine [CP] 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 h without affecting the reaction of the subepicardial and subendocardial cells. CP also inhibited the 2nd phase of Ca2+ accumulation. An accelerated degradation of phospholipids [PL] was observed with a 33% decrease in total phospholipids by 12 h. Phosphatidylethanolamine was reduced by 50% and phosphatidylcholine by 25% without increases in the corresponding lysophospholipids. CP prevented the accelerated degradation and consequent loss of PL. Isolated sarcoplasmic reticulum showed a time-dependent loss of PL with a parallel loss of active Ca2+ uptake that reached 60% with a total lipid depletion from these membranes of 33% by 12 h. Twelve-hour ischemic sarcoplasmic reticulum exhibited a 6-7-fold increase in passive permeability to Ca2+. CP protected against the loss of PL, the inhibition of Ca2+ uptake, and the increased Ca2+ permeability of the sarcoplasmic reticulum. Rat myocardial cells apparently react to lethal doses of ischemia in a manner similar to the reaction of liver cells. The evidence implies that a disturbance in PL metabolism and its associated membrane dysfunction is the critical alteration that produces irreversible cell injury in ischemia.