Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection?

Yongge Liu, Toshiaki Sato, Brian O'Rourke, Eduardo Marban

Research output: Contribution to journalArticle

Abstract

Background - Brief interruptions of coronary blood flow paradoxically protect the heart from subsequent prolonged ischemia. The basis of such endogenous cardioprotection, known as 'ischemic preconditioning,' remains uncertain. Pharmacological evidence has implicated ATP-dependent potassium (K(ATP)) channels in the mechanism of preconditioning; however, the effects of sarcolemmal K(ATP) channels on excitability cannot account for the protection. Methods and Results - 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, selectively activates mitochondrial K(ATP) channels. Diazoxide induced reversible oxidation of flavoproteins with an EC50 of 27 μmol/L but did not activate sarcolemmal K(ATP) channels. The subcellular site of diazoxide action is further localized to mitochondria by confocal imaging of fluorescence arising from flavoproteins and tetramethylrhodamine ethyl ester. In a cellular model of simulated ischemia, inclusion of diazoxide decreased the rate of cell death to about half of that in controls. Both the redox changes and protection are inhibited by the K(ATP) channel blocker 5-hydroxydecanoic acid. Conclusions - Our results demonstrate that diazoxide targets mitochondrial but nor sarcolemmal K(ATP) channels and imply that mitochondrial K(ATP) channels may mediate the protection from K(ATP) channel openers.

Original languageEnglish (US)
Pages (from-to)2463-2469
Number of pages7
JournalCirculation
Volume97
Issue number24
DOIs
StatePublished - Jun 23 1998

Keywords

  • Ischemia
  • Mitochondria
  • Potassium channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection?'. Together they form a unique fingerprint.

  • Cite this