Models of Injury of Cardiovascular Membranes by Amphiphiles and Free Radicals

Abstract

Current evidence from ultrastructural, biochemical and electrophysiological studies suggest that membrane damage is an early event in ischemic myocardial injury (1–3). Previous investigations (4–8) suggest that sarcolemmal, microsomal and lysosomal structural and functional integrity may be compromised by any one or combinations of mechanisms that may be active during ischemia. During ischemia, cellular membranes may be subjected to perturbations by accumulated lipid metabolites, elevated levels of free radicals and activated lipolytic enzymes. We have investigated the molecular nature of several injurious processes in vitro in an effort to determine the potential sequence of events leading to ischemic membrane damage. Incubation of highly purified hepatic lysosomes at acid pH results in loss of lysosomal latency and leakage of lysosomal lipases. When the sarcolemmal (SL) membranes from canine myocytes were incubated with the soluble lysosomal enzymes, the membrane phospholipids were differentially hydrolyzed. In the presence of a .0₂− driven (derived from dihydroxyfumarate) iron catalyzed-free radical generating system, the SL membrane fluidity was altered. The peroxidation of the SL membrane was accompanied by a selective loss of phospholipids and the membrane-bound Na,K-ATPase was also inactivated.