(Circulation. 2000;102:800.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Adenosine Primes the Opening of Mitochondrial ATP-Sensitive Potassium Channels
A Key Step in Ischemic Preconditioning?
From the Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Md. Dr Sato is now at the Department of Physiology, Oita Medical University, Hasama, Oita, Japan.
Correspondence to Eduardo Marbán, MD, PhD, Institute of Molecular Cardiobiology, Johns Hopkins University, Ross 844/720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}jhmi.edu
Background—Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (KATP) 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 KATP channel activity in intact rabbit ventricular myocytes. Adenosine (100 µmol/L) increased mitochondrial KATP channel activity and abbreviated the latency to mitochondrial KATP 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 KATP channel activation, because they could be blocked by the mitochondrial KATP 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 KATP channel blocker HMR1098. Moreover, adenosine augmented the cardioprotective effect of diazoxide. A quantitative model of mitochondrial KATP channel gating reproduced the major experimental findings.
Conclusions—Our results support the hypothesis that adenosine receptor activation primes the opening of mitochondrial KATP channels in a protein kinase C–dependent manner. The findings provide tangible links among various key elements in the preconditioning cascade.
Key Words: adenosine • ischemia • ion channels • mitochondria
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