Published Online
on November 1, 2004

A more recent version of this article appeared on November 9, 2004

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Submitted on January 21, 2004
Revised on May 20, 2004
Accepted on June 10, 2004

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

Fikret Er MD, Guido Michels MD, Natig Gassanov MD, Francisco Rivero MD, and Uta C. Hoppe MD^*

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.

^* To whom correspondence should be addressed. E-mail: uta.hoppe{at}uni-koeln.de.

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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