Background— Whereas in the past, androgens were mainly believed to exert adverse effects on the cardiovascular system, recent experimental data postulate a benefit of testosterone for recovery of myocardial function after ischemia/reperfusion injury. Thus, we examined whether testosterone might improve myocardial tolerance to ischemia due to activation of mitochondrial (mitoK_ATP) and/or sarcoplasmatic (sarcK_ATP) K_ATP channels.

Methods and Results— In a cellular model of ischemia, testosterone significantly decreased the rate of ischemia-induced death of cardiomyocytes that could be prevented by 5-hydroxydecainoic acid but was unaffected by the sarcK_ATP blocker HMR1098 and the testosterone receptor antagonist flutamide. To index mitoK_ATP, mitochondrial flavoprotein fluorescence was measured. Testosterone induced a highly significant increase in mitochondrial flavoprotein fluorescence in intact myocytes and isolated mitoplasts that could be abolished by 5-hydroxydecainoic acid. Testosterone-mediated flavoprotein oxidation of mitoplasts was K⁺ dependent and ATP sensitive. In mitoplast-attached single-channel recordings, testosterone directly activated an ATP-sensitive K⁺ channel of the inner mitochondrial membrane. Addition of the K_ATP channel opener diazoxide and pinacidil to the cytosolic solution activated the ATP-sensitive K⁺ current comparable to testosterone, whereas 5-hydroxydecainoic acid and glibenclamide inhibited the testosterone-induced current. Patch-clamp experiments of intact myocytes in whole-cell configuration did not demonstrate any effect of testosterone on sarcK_ATP channels.

Conclusions— Our results provide direct evidence for the existence of cardiac mitoK_ATP and a link between testosterone-induced cytoprotection and activation of mitoK_ATP. Endogenous testosterone might play a more important role in recovery after myocardial infarction than is currently assumed.