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

Abstract

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 24Ϯ4% 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 (Ͻ10 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 (Ն20 minutes) would have allowed assessment of the involvement of mitochondrial versus sarcolemmal K ϩ 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 ResponseWe thank Drs Duncker and Verdouw for their interest in our article 1 and their comments with respect to the interpretation of the results.Our study was conducted to determine whether diazoxideinduced protective effect on the ischemia-induced contractile dysfunction could be observed in the heart of sarcolemmal K ATP channel-deficient mice. The findings of the study suggested that activation of sarcolemmal K ATP channels rather than mitochondrial K ATP channels is important for the cardioprotective effect of diazoxide in mouse hearts. 1 We measured the left ventricular function during 20-minute ischemia followed by 60-minute reperfusion and found that diazoxide improved the contractile dysfunction in wildtype but not Kir6.2 knockout hearts. The stunned myocardium is defined as "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." 2 As pointed out by Duncker and Verdouw, the 20-minute global ischemia might have produced irreversible as well as reversible myocardial damage in isolated mouse hearts. The discrimination between reve...

The role of mitochondria in protection of the heart by preconditioning

“…This is especially true of the K ATP channel opener diazoxide that has been reported to show a sensitivity towards the mitochondrial K ATP channel at least three orders of magnitude greater than for the sarcolemmal K ATP channel whilst 5-hydroxydecanoate (5HD) blocks the mitochondrial channel whilst having little effect on the sarcolemmal one [167,168] . However, there are other data claiming that diazoxide will open and 5HD block plasma membrane K ATP channels at the concentrations frequently used to modulate mitochondrial K ATP channels when investigating their possible role in cardioprotection [191–194] .…”

KATP channels are regulators of programmed cell death and targets for the creation of novel drugs against ischemia/reperfusion cardiac injury

“…Initially, it was assumed that the cardioprotective effect of KCOs is mediated via mitoKATP channel opening [59, 60, 69, 85, 198, 228, 253, 264, 287]. However, then there were articles whose authors obtained convincing evidence of the involvement of the sarcKATP channel in a KCO‐induced increase in cardiac tolerance to I/R [83, 288–290]. Consequently, both KATP channels can be involved in the infarct‐reducing effect of KCOs.…”