Terikalant, an Inward-rectifier Potassium Channel Blocker, does not Abolish the Cardioprotection Induced by Ischemic Preconditioning in the Rat

Recent results have shown that the sulfonylurea receptor couples to several types of inward-rectifier potassium (KIR) channels, which suggests that sensitivity to blockade of a pathophysiological phenomenon such as ischemic preconditioning (PC) by glibenclamide may not be the result of this compound selectively blocking the ATP-sensitive potassium (KATP) channel. Therefore, to address this possibility, a role for myocardial KIRvKATPchannels in ischemic PC was evaluated in the rat. To test this hypothesis, anesthetized, open-chest, male Wistar rats were assigned to one of seven experimental protocols. Animals assigned to group I (control) received 30 min of occlusion and 2 h of reperfusion. Ischemic PC was produced by 3×5-min occlusion and 2-h reperfusion periods (group II). Terikalant (TK), an inward-rectifier potassium channel blocker, was used to test the role of other K+channels, most notably the KIR, in the cardioprotective effect of ischemic PC in the rat. TK was given at a dose of 3 mg/kg, i.v., 15 min before the prolonged occlusion and reperfusion periods (group III). In groups IV, V, and VI terikalant (1, 3 and 6 mg/kg, i.v.) was given 15 min before ischemic PC (lowTK+PC, medTK+PC and hiTK+PC, respectively). Group VII consisted of glibenclamide (0.3 mg/kg, i.v.) given 30 min prior to ischemic PC (GLY+PC). Infarct size (IS) as a percent of the area at risk (AAR) was measured using the histochemical stain, 2,3,5-triphenyltetrazolium chloride. The average IS/AAR for the control was 49.9±2.1%. Ischemic PC markedly reduced infarct size (8.6±1.8%; *P<0.05vcontrol). Terikalant (TK; 1, 3 and 6 mg/kg, i.v.) did not abolish the cardioprotective effect of ischemic PC at any dose (15.5±6.4, 16.4±5.2 and 8.8±1.6%, respectively; *P<0.05vcontrol). TK itself had no effect on infarct size. GLY completely abolished the cardioprotective effect of ischemic PC (48.2±6.4%). In addition, the high dose of TK significantly (P<0.05) increased the action potential duration at 50% repolarization from 48±3 to 64±4 ms and 30μmof TK, a concentration which produced a 39% decrease in the inward-rectifier potassium channel current in isolated guinea-pig ventricular myocytes in the whole-cell patch-clamp mode did not block the increase in KATPcurrent produced by the KATPopener bimakalim (3μm). These results demonstrate that although the myocardial KATPchannel belongs to the KIRsuperfamily, the endogenous myocardial KIRchannel does not mediate ischemic PC in the rat heart; however, the KATPchannel does mediate its cardioprotective effect.