Adenosine primes the opening of mitochondrial ATP-sensitive potassium channels: A key step in ischemic preconditioning?

Toshiaki Sato, Norihito Sasaki, Brian O'Rourke, Eduardo Marbán

Research output: Contribution to journalArticlepeer-review

Abstract

Background - Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (K(ATP)) channels have emerged as the likely effectors. We sought to determine the mechanistic interactions between these 2 observations. Methods and Results - The mitochondrial flavoprotein oxidation induced by diazoxide (100 μmol/L) was used to quantify mitochondrial K(ATP) channel activity in intact rabbit ventricular myocytes. Adenosine (100 μmol/L) increased mitochondrial K(ATP) channel activity and abbreviated the latency to mitochondrial K(ATP) channel opening. These potentiating effects were entirely prevented by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (100 μmol/L) or by the protein kinase C inhibitor polymyxin B (50 μmol/L). The effects of adenosine and diazoxide reflected mitochondrial K(ATP) channel activation, because they could be blocked by the mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (500 μmol/L). In a cellular model of simulated ischemia, adenosine mitigated cell injury; this cardioprotective effect was blocked by 5-hydroxydecanoate but not by the surface-selective K(ATP) channel blocker HMR1098. Moreover, adenosine augmented the cardioprotective effect of diazoxide. A quantitative model of mitochondrial K(ATP) channel gating reproduced the major experimental findings. Conclusions - Our results support the hypothesis that adenosine receptor activation primes the opening of mitochondrial K(ATP) channels in a protein kinase C - dependent manner. The findings provide tangible links among various key elements in the preconditioning cascade.

Original languageEnglish (US)
Pages (from-to)800-805
Number of pages6
JournalCirculation
Volume102
Issue number7
DOIs
StatePublished - 2000

Keywords

  • Adenosine
  • Ion channels
  • Ischemia
  • Mitochondria

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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