Diazoxide-Induced Cardioprotection Requires Signaling Through a Redox-Sensitive Mechanism

作者：Robert A. Forbes, Charles Steenbergen, Elizabeth Murphy · 发表于：Circulation Research · 年份：2001 · DOI：10.1161/hh0801.089342 · 被引用次数：393 · 研究领域：Cardiac Ischemia and Reperfusion、Cardiac Arrest and Resuscitation、Cardiac electrophysiology and arrhythmias

Diazoxide, a selective opener of the mitochondrial ATP-sensitive potassium channel, has been shown to elicit tolerance to ischemia in cardiac myocytes and in perfused heart. However, the mechanism of this cardioprotection is poorly understood. Because reactive oxygen species (ROS) are recognized as important intracellular signaling molecules and have been implicated in ischemic preconditioning, we examined diazoxide-induced ROS production in adult cardiomyocytes. Cells treated with 50 micromol/L diazoxide showed a 173% increase in ROS production relative to baseline. 5-Hydroxydecanoate was found to attenuate the diazoxide-induced increase in ROS generation. The diazoxide-induced increase in ROS also was abrogated by the addition of either the antioxidant N-acetylcysteine (NAC) or N-mercaptopropionylglycine. We also examined the ability of NAC to block the protective effects of diazoxide in the perfused rat heart. After 20 minutes of global ischemia and 20 minutes of reflow, hearts perfused with 100 micromol/L diazoxide before ischemia showed significantly improved postischemic contractile function relative to untreated hearts (84% versus 29% of initial left ventricular developed pressure, respectively). Hearts treated with diazoxide in the presence of 4 mmol/L NAC recovered 53% of initial left ventricular developed pressure, whereas hearts treated with NAC alone recovered 46% of preischemic function. Using (31)P NMR spectroscopy, we found that, similar to preconditioning, dia...