TERIKALANT, AN INWARD-RECTIFIER POTASSIUM CHANNEL BLOCKER, DOES NOT ABOLISH THE CARDIOPROTECTION INDUCED BY ISCHEMIC PRECONDITIONING IN THERAT

Recent results have shown that the sulfonylurea receptor couples to se veral types of inward-rectifier potassium (K-IR) channels, which sugge sts that sensitivity to blockade of a pathophysiological phenomenon su ch as ischemic preconditioning (PC) by glibenclamide may not be the re sult of this compound selectively blocking the ATP-sensitive potassium (K-ATP) channel. Therefore, to address this possibility, a role for m yocardial K-IR nu K-ATP channels in ischemic PC was evaluated in the r at. To test this hypothesis, anesthetized, open-chest, male Wistar rat s were assigned to one of seven experimental protocols, Animals assign ed to group I (control) received 30 min of occlusion and 2 h of reperf usion. Ischemic PC was produced by 3 x 5-min occlusion and 2-h reperfu sion periods (group II), Terikalant (TK), an inward-rectifier potassiu m channel blocker, was used to test the role of other I(+ channels, mo st notably the K-IR, 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 pr olonged 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 i schemic 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 is chemic PC (GLY + PC), Infarct size (IS) as a percent of the area at ri sk (AAR) was measured using the histochemical stain, 2,3, 5-triphenylt etrazolium chloride. The average IS/AAR for the control was 49.9 +/- 2 .1%. Ischemic PC markedly reduced infarct size (8.6 +/- 1.8%; P<0.05 nu control). Terikalant TK; 1, 3 and 6 mg/kg, i.v.) did not abolish t he cardioprotective effect of ischemic PC at any dose (15.5 +/- 6.4, 1 6.4 +/- 5.2 and 8.8 +/- 1.6%, respectively: P<0.05 nu control). TK i tself had no effect on infarct size. GLY completely abolished the card ioprotective effect of ischemic PC (48.2 +/- 6.4%), In addition, the h igh dose of TI( significantly (P<0.05) increased the action potential duration at 50% repolarization from 48 +/- 3 to 64 +/- 4 ms and 30 mu M of TK, a concentration which produced a 39% decrease in the inward-r ectifier potassium channel current in isolated guinea-pig ventricular myocytes in the whole-cell patch-clamp mode did not block the increase in K-ATP current produced by the K-ATP opener bimakalim (3 mu M). The se results demonstrate that although the myocardial K-ATP channel belo ngs to the K-IR superfamily, the endogenous myocardial K-IR channel do es not mediate ischemic PC in the rat heart: however, the K-ATP, chann el does mediate its cardioprotective effect. (C) 1998 Academic Press