PROTECTIVE EFFECTS AGAINST HYDROGEN PEROXIDE-INDUCED TOXICITY BY ACTIVATORS OF THE ATP-SENSITIVE POTASSIUM CHANNEL IN ISOLATED RAT HEARTS

Activation of ATP-sensitive (K-ATP) channels has been shown to exert p rotective effects on the ischemic and reperfused myocardium. Reactive oxygen species are thought to mediate, at least in part, this form of cardiac injury. Using isolated perfused rat hearts, we therefore studi ed whether K, activation exerts any effect on the direct deleterious e ffects of either 200 mu M hydrogen peroxide or a free radical generati ng system consisting of purine plus xanthine oxidase in terms of funct ion and energy metabolite status, On their own, hydrogen peroxide or t he combination of purine plus xanthine oxidase treatment resulted in a time-dependent depression of myocardial contractility, which reached over 90% after 30 min perfusion, an effect which was associated with a pproximately 1000% elevation in left ventricular end-diastolic pressur e (LVEDP). The K-ATP channel opener cromakalim (0.5 mu M) significantl y attenuated the hydrogen peroxide-induced loss in systolic function t hroughout the treatment period, and reduced the elevation in LVEDP wit h significant attenuation 10, 15 and 20 min after hydrogen peroxide ad dition. Contractile dysfunction produced by hydrogen peroxide was asso ciated with significantly reduced tissue ATP, creatine phosphate and g lycogen content to approximately 70, 60 and 70% of control, respective ly. The depletion of these metabolites was significantly attenuated to 35, 23 and 23% of control, respectively, in the presence of cromakali m. The protective effects of cromakalim against contractile dysfunctio n, as well as depletion in intermediary energy metabolites, was abolis hed in the presence of the K, channel antagonist glibenclamide (1 mu M ). However, glibenclamide on its own failed to alter the cardiac respo nse to hydrogen peroxide with respect to any parameter, The responses to the free radical generating system consisting of purine plus xanthi ne oxidase was unaffected by cromakalim, Our study shows that It, chan nel activation selectively protects against the cardiotoxic influence of hydrogen peroxide, and may explain, in part,the salutary effects of K-ATP activators in myocardial ischemia. (C) 1998 Academic Press Limi ted.