Investigations Of The Mechanism Of Alcohol-induced Cardiomyopathy

Investigations into the mechanism of severe, subacute ethanol induced cardiomyopathy in the rat were performed in animals that were severely intoxicated for 48 hours. This treatment produced increases in cardiac wet weight, dry weight and protein content. Determination of cardiac DNA content and water content showed that the increase in heart size resulted from hypertrophy and not hyperplasia nor edema.;In a time effect study of intracellular events it was found that cardiac ornithine decarboxylase activity was enhanced after eight hours of intoxication and remained elevated through 24 hours. RNA content was elevated by eight hours and remained high through the 48 hour intoxication period. These changes were followed by increases in cardiac protein (16 hours) and this measure continued to increase through the remainder of the period of intoxication. Wet heart weights were significantly elevated by 24 hours and continued to increase through 48 hours. Enhanced activition of ornithine decarboxylase was shown to be a major contributor to the initiation of the hypertrophic response as the selective inhibitor of this enzyme, difluoromethylornithine, abolished the increases in all measured cardiac parameters.;The role of activation of cardiac {dollar}\beta{dollar}-adrenoceptors in the development of the hypertrophy was assessed through the use of a number of antagonists. Treatments which incorporated antagonism of both {dollar}\beta{dollar}-adrenoceptor subtypes found in the heart suppressed the increases in cardiac parameters, whereas treatments with specific antagonists of {dollar}\beta\sb1{dollar}- or {dollar}\beta\sb2{dollar}-adrenoceptor subtypes, given alone, were ineffective. Additionally, cardiac membrane stabilization, a property often possessed by {dollar}\beta{dollar}-adrenoceptor antagonists, was unable to abolish the increases in measured parameters.;Severe, subacute, ethanol intoxication produced a number of lesions of the myocardium. These included focal necrosis, thrombi with necrosis, infiltration of inflammatory cells, mitochondrial degeneration, contracture and dehiscence of the intercalated discs. Determination of creatine kinase showed no significant level of myocyte rupture. Treatment with D,L-propranolol, in doses which suppressed the development of the cardiac hypertrophy, did not alter the development of myocardial lesions, suggesting a dissociation between the two phenomena