Mitochondrial ATP-dependent potassium channels. Viable candidate effectors of ischemic preconditioning

Yongge Liu, Toshiaki Sato, Jegatheesan Seharaseyon, Adam Szewczyk, Brian O'Rourke, Eduardo Marbán

Research output: Contribution to journalArticle

Abstract

Pharmacological evidence has implicated ATP-dependent potassium (K(ATP)) channels in the mechanism of ischemic preconditioning; however, the effects of sarcolemmal K(ATP) channels on excitability cannot account for the protection. K(ATP) channels also exist in mitochondrial inner membrane. To test whether such channels play a role in cardioprotection, we simultaneously measured flavoprotein fluorescence, an index of mitochondrial redox state, and sarcolemmal K(ATP) currents in intact rabbit ventricular myocytes. Our results show that diazoxide, a K(ATP) channel opener, induced reversible oxidation of flavoproteins, but did not activate sarcolemmal K(ATP) channels. This effect of diazoxide was blocked by 5-hydroxydecanoic acid (5-HD). We further verified that 5-HD is a selective blocker of the mitochondrial K(ATP) channels. These methods have enabled us to demonstrate that the activity of mitochondrial K(ATP) channels can be regulated by protein kinase C. In a cellular model of simulated ischemia, inclusion of diazoxide decreased the rate of cell death to about half of that in control. Such protection is inhibited by 5-HD. In conclusion, our results demonstrate that diazoxide targets mitochondrial but not sarcolemmal K(ATP) channels, and imply that mitochondrial K(ATP) channels may mediate preconditioning.

Original languageEnglish (US)
Pages (from-to)27-37
Number of pages11
JournalAnnals of the New York Academy of Sciences
Volume874
DOIs
StatePublished - Jan 1 1999

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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