Responsiveness of cardiac adenylate cyclase in the normal and ischemic myocardium. Role of oxygen free radicals.

Cyclic AMP has been shown to play a significant regulatory role in a number of myocardial cell functions. The cAMP-forming adenylate cyclase complex is localized in the sarcolemmal membrane which is the major site of lipid peroxidation by oxygen-derived free radicals known to be increased in the ischemic myocardium. Adenylate cyclase function was found to be depressed in the ischemic myocardium but the specific biochemical mechanism responsible for this effect is still unknown. Therefore, the effect of free radical formation on adenylate cyclase was studied. Highly purified sarcolemmal membranes, exhibiting an NaF-stimulated activity of 3.46 +/- 0.65 nmol cAMP formed min-1 mg-1 of protein, were exposed to free radicals formation of which was induced by Fe++/ascorbate. A rapid loss of adenylate cyclase activation by 1-isoproterenol, NaF, and Gpp(NH)p has been observed. Concentration of malondialdehyde (MAD), a key intermediate in the formation of peroxides, was positively correlated to the rapid loss of adenylate cyclase activity. As result, adenylate cyclase was found to be highly susceptible to free radical-induced damage. It is thought that this effect might be one of the causes of the biochemical dearrangements contributing to the alteration of sarcolemmal membrane function in myocardial ischemia resulting in the reduction or loss of metabolic and contractile regulation of the heart.