Protective effects against hydrogen peroxide-induced toxicity by activators of the ATP-sensitive potassium channel in isolated rat hearts.
Activation of ATP-sensitive (KATP) channels has been shown to exert protective 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 studied whether KATP activation exerts any effect on the direct deleterious effects of either 200 microM hydrogen peroxide or a free radical generating system consisting of purine plus xanthine oxidase in terms of function and energy metabolite status. On their own, hydrogen peroxide or the 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 approximately 1000% elevation in left ventricular end-diastolic pressure (LVEDP). The KATP channel opener cromakalim (0.5 microM) significantly attenuated the hydrogen peroxide-induced loss in systolic function throughout the treatment period, and reduced the elevation in LVEDP with significant attenuation 10, 15 and 20 min after hydrogen peroxide addition. Contractile dysfunction produced by hydrogen peroxide was associated with significantly reduced tissue ATP, creatine phosphate and glycogen content to approximately 70, 60 and 70% of control, respectively. The depletion of these metabolites was significantly attenuated to 35, 23 and 23% of control, respectively, in the presence of cromakalim. The protective effects of cromakalim against contractile dysfunction, as well as depletion in intermediary energy metabolites, was abolished in the presence of the KATP channel antagonist glibenclamide (1 microM). However, glibenclamide on its own failed to alter the cardiac response to hydrogen peroxide with respect to any parameter. The responses to the free radical generating system consisting of purine plus xanthine oxidase was unaffected by cromakalim. Our study shows that KATP channel activation selectively protects against the cardiotoxic influence of hydrogen peroxide, and may explain, in part, the salutary effects of KATP activators in myocardial ischemia.
Gan
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Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Cook
M A
MA
Moffat
M P
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Karmazyn
M
M
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D019806:Cromakalim / Q000008:administration & dosage; D005609:Free Radicals; D005905:Glyburide / Q000008:administration & dosage; D006003:Glycogen / Q000032:analysis; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010725:Phosphocreatine / Q000032:analysis; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000008:administration & dosage; D017725:Ventricular Pressure / Q000187:drug effects; D014969:Xanthine Oxidase / Q000494:pharmacology
D005609:Free Radicals; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011687:Purines; D014665:Vasodilator Agents; D010725:Phosphocreatine; D019806:Cromakalim; D000255:Adenosine Triphosphate; D006003:Glycogen; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D005905:Glyburide