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

Article

关键词: PROTEIN-KINASE-C;    K+ CHANNELS;    SODIUM 5-HYDROXYDECANOATE;    VENTRICULAR MYOCYTES;    RABBIT HEART;    MODULATION;    DOGS;    CARDIOPROTECTION;    ANTAGONIST;    PROTECTION;   

DOI  :  10.1161/01.CIR.102.7.800

来源: SCIE

【 摘 要 】

Background-Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (K-ATP) channels have emerged as the likely effecters. We sought to determine the mechanistic interactions between these 2 observations. Methods and Results-The mitochondrial flavoprotein oxidation induced by diazoxide (100 mu mol/L) was used to quantify mitochondrial K-ATP channel activity in intact rabbit ventricular myocytes. Adenosine (100 mu mol/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 mu mol/L) or by the protein kinase C inhibitor polymyxin B (50 mu mol/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 mu mol/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.

【 授权许可】

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