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

Abstract.

The roles of sarcolemmal ATP-sensitive K⁺ (sarcK_ATP) and mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channels in the cardioprotection induced by K_ATP channel openers remain unclear, though the mitoK_ATP 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 sarcK_ATP and mitoK_ATP channels were used to examine the role of each channel subtype in infarct size limitation by K_ATP channel openers.

Isolated rabbit hearts were perfused in the Langendorff mode with monitoring of the activation recovery interval (ARI) and subjected to 30-min global ischemia/2-h reperfusion to induce infarction. Before ischemia, hearts received 10 µM pinacidil, 100 µM diazoxide, or PC with or without preceding infusion of a sarcK_ATP channel-selective blocker (5 µM HMR1098) or a mitoK_ATP channel-selective blocker (100 µM 5-hydroxydecanoate, 5-HD). ARI, an index of action potential duration, was shortened from 118±3 ms to 77±5 ms after 10 min of ischemia in untreated control hearts. Pinacidil shortened ARI before ischemia from 113±2 ms to 78±5 ms and enhanced the ARI shortening during ischemia. Diazoxide did not affect ARI before ischemia but accelerated ischemia-induced shortening of ARI. Infarct size as a percentage of the left ventricle (%IS/LV) was reduced by pinacidil and diazoxide from the control value of 47.2±4.0% to 4.5±1.5% and 5.2±1.2%, respectively. HMR1098 significantly inhibited the shortening of ARI by ischemia, pinacidil and diazoxide and partially blocked infarct size limitation by these K_ATP channel openers (%IS/LV=32.6±4.2% and 23.4±5.3%, respectively). Infusion of 5-HD did not modify the change in ARI caused by the K_ATP channel openers but completely abolished cardioprotection (%IS/LV=46.0±6.2% with pinacidil and 57.2±7.0% with diazoxide). PC with two episodes of 5-min ischemia limited %IS/LV to 21.6±4.0%, and this protection was not inhibited by HMR1098. Neither HMR1098 nor 5-HD alone modified infarct size.

In conclusion, both sarcK_ATP and mitoK_ATP channels may contribute to the anti-infarct tolerance afforded by pinacidil and diazoxide.