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
KATP 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 microM
pinacidil, 100 microM
diazoxide, or PC with or without preceding infusion of a sarcK(
ATP) channel-selective blocker (5 microM HMR1098) or a
mitoK(ATP) channel-selective blocker (100 microM 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.