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(Circulation. 2004;110:3100-3107.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Testosterone Induces Cytoprotection by Activating ATP-Sensitive K⁺ Channels in the Cardiac Mitochondrial Inner Membrane

From the Department of Internal Medicine III (F.E., G.M., N.G., U.C.H.), Center of Biochemistry I (F.R.), and Center for Molecular Medicine (G.M., F.R., U.C.H.), University of Cologne, Cologne, Germany.

Correspondence to Uta C. Hoppe, MD, Department of Internal Medicine III, University of Cologne, Joseph Stelzmann Strasse 9, 50924 Cologne, Germany. E-mail uta.hoppe{at}uni-koeln.de

Received January 21, 2004; de novo received May 20, 2004; accepted June 10, 2004.

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.

Key Words: ion channels • hormones • myocytes • preconditioning • electrophysiology

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