Contribution of both the sarcolemmal KATP and mitochondrial KATP channels to infarct size limitation by KATP channel openers: differences from preconditioning in the role of sarcolemmal KATP channels

摘要

The roles of sarcolemmal ATP-sensitive K+ (sarcKATP) and mitochondrial ATP-sensitive K+ (mitoKATP) channels in the cardioprotection induced by KATP channel openers remain unclear, though the mitoKATP channel has been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning (PC). In the present study, selective inhibitors of the sarcKATP and mitoKATP channels were used to examine the role of each channel subtype in infarct size limitation by KATP channel openers.nIsolated rabbit hearts were perfused in the Langendorffnmode with monitoring of the activation recovery intervaln(ARI) and subjected to 30-min global ischemia/2-h reperfusionnto induce infarction. Before ischemia, hearts receivedn10 μM pinacidil, 100 μM diazoxide, or PC with ornwithout preceding infusion of a sarcKATP channel-selectivenblocker (5 μM HMR1098) or a mitoKATP channel-selectivenblocker (100 μM 5-hydroxydecanoate, 5-HD).nARI, an index of action potential duration, was shortenednfrom 118±3 ms to 77±5 ms after 10 min of ischemia innuntreated control hearts. Pinacidil shortened ARI beforenischemia from 113±2 ms to 78±5 ms and enhanced thenARI shortening during ischemia. Diazoxide did not affectnARI before ischemia but accelerated ischemia-inducednshortening of ARI. Infarct size as a percentage of the leftnventricle (%IS/LV) was reduced by pinacidil and diazoxidenfrom the control value of 47.2±4.0% to 4.5±1.5% andn5.2±1.2%, respectively. HMR1098 significantly inhibitednthe shortening of ARI by ischemia, pinacidil and diazoxidenand partially blocked infarct size limitation by thesenKATP channel openers (%IS/LV=32.6±4.2% and 23.4±n5.3%, respectively). Infusion of 5-HD did not modify thenchange in ARI caused by the KATP channel openers butncompletely abolished cardioprotection (%IS/LV=46.0±n6.2% with pinacidil and 57.2±7.0% with diazoxide). PCnwith two episodes of 5-min ischemia limited %IS/LV ton21.6±4.0%, and this protection was not inhibited bynHMR1098. Neither HMR1098 nor 5-HD alone modifiedninfarct size.nIn conclusion, both sarcKATP and mitoKATP channelsnmay contribute to the anti-infarct tolerance afforded bynpinacidil and diazoxide.