title: Testosterone induces cytoprotection by activating ATP-sensitive K+ channels in the cardiac mitochondrial inner membrane.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Internal Medicine III, University of Cologne, Cologne, Germany.
authors.forename: Fikret
authors.initials: F
authors.lastname: Er
authors.forename: Guido
authors.initials: G
authors.lastname: Michels
authors.forename: Natig
authors.initials: N
authors.lastname: Gassanov
authors.forename: Francisco
authors.initials: F
authors.lastname: Rivero
authors.forename: Uta C
authors.initials: UC
authors.lastname: Hoppe
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D059002:Androgen Receptor Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C117780:mitochondrial K(ATP) channel; D013739:Testosterone; D000735:Androstenedione; D005485:Flutamide; D020110:Pinacidil; D000255:Adenosine Triphosphate; D003981:Diazoxide; D011188:Potassium