Cardioprotective Effect of Diazoxide Is Mediated by Activation of Sarcolemmal but not Mitochondrial ATP-Sensitive Potassium Channels in Mice

by Activation of Sarcolemmal but not Mitochondrial ATP-Sensitive Potassium Channels in Mice To the Editor: Recently, Suzuki et al1 reported that attenuation of myocardial stunning by diazoxide in mice was mediated through activation of sarcolemmal rather than mitochondrial K ATP channels. Although the authors used an elegant approach by combining both pharmacological tools (utilizing the mitochondrial K ATP-channel inhibitor 5-hydroxydecanoate and the sarcolemmal K ATP channel inhibitor HMR-1098) and molecular tools (sarcolemmal K ATP channel [Kir6.2]–deficient mice), interpretation of the results is difficult. Thus, the authors claim to have investigated the protective effects of pretreatment with diazoxide against myocardial stunning, produced by 20 minutes of no-flow global ischemia in isolated buffer-perfused hearts. However, stunning is defined as reversible myocardial dysfunction that persists after a brief period of ischemia despite full reperfusion. In isolated buffer-perfused rodent hearts, 20 minutes of ischemia already results in significant cardiac necrosis. For instance, 20 minutes of global cardiac ischemia in mice resulted in 24 4% necrosis of the left ventricle.2 As an unfortunate consequence of this, the diazoxide-induced improvement in recovery of left ventricular contractile function (during the subsequent 60 minutes of reperfusion) in the wild-type control mice cannot simply be ascribed to attenuation of stunning, because it could also have resulted from limitation of myocardial infarct size.3,4 The authors should therefore have chosen a brief period of ischemia ( 10 minutes) that results in pure stunning without infarction.5 In such a protocol, an additional group that received diazoxide just before reperfusion would have allowed further delineation between antiischemic and possible reperfusion injury–limiting effects of diazoxide in stunning. Alternatively, the authors could have supported their conclusions by demonstrating a lack of effect of diazoxide on infarct size. This is, however, unlikely in view of the reported infarct size–limiting effect of diazoxide in mice.4 Rather, studying additional groups subjected to a long period of ischemia ( 20 minutes) would have allowed assessment of the involvement of mitochondrial versus sarcolemmal K ATP channels in the infarct size–limiting effects of diazoxide.3,4 Finally, diazoxide was administered in a concentration of 100 mol/L. A concentration of 30 mol/L may already produce a maximal effect, and a further increase to 100 mol/L may be associated with loss of mitochondrial K ATP channel selectivity.3,4 Hence, studying doses of 30 and 100 mol/L in both brief and long ischemia protocols would have provided valuable additional information on the role of mitochondrial versus sarcolemmal K ATP channels in the protection by diazoxide against reversible and irreversible myocardial damage in mice.