GLIBENCLAMIDE, A BLOCKER OF ATP-SENSITIVE POTASSIUM CHANNELS, ABOLISHES INFARCT SIZE LIMITATION BY PRECONDITIONING IN RABBITS ANESTHETIZED WITH XYLAZINE PENTOBARBITAL BUT NOT WITH PENTOBARBITAL ALONE

The role of ATP-sensitive potassium channels (K-ATP) in the mechanism of ischemic preconditioning (PC) is controversial, partly because descriptions of inhibition of PC by K-ATP blockers in the literature are inconsistent, We sought a reason for the discrepant findings regarding the effects of glibenclamide (Glib), a specific blocker of K-ATP in preventing the reduction of infarct size (IS) induced by PC, The effect of Glib pretreatment (0.3 mg/kg i.v.) on PC was examined in three conditions: (a) when PC was performed with 3- and 5-min ischemia (i.e., potency of PC differs), (b) when rabbits were pretreated with prazosin and metoprolol (0.15 mg/kg i.v. each) to reduce myocardial O-2 consumption, and (c) when xylazine was added to pentobarbital anesthesia. In rabbits under pentobarbital anesthesia, the left coronary artery was occluded for 30 min and then reperfused. The area at risk (AAR) and IS were determined 72 h after reperfusion in the first series of experiments and 3 h after reperfusion in the second and third series. IS as a percentage of AAR (%IS/AR) were 31.7 +/- 2.8 and 19.6 +/- 2.5% (SEM) after PC with 3- and 5-min ischemia, respectively, values significantly smaller than %IS/AR in the untreated control group (49.2 +/- 3.3%). The limitation of IS observed with 3- or 5-min PC was not prevented by Glib. Glib also failed to block %IS/AR reduction by PC, even when rate-pressure product (RPP) was reduced to similar to 65% by prazosin/metoprolol (Praz/Met) pretreatment. When xylazine (6 mg/kg i.v.) was added to the anesthetic regimen, however, PC with 5-min ischemia failed to limit %IS/AR significantly in Glib-pretreated hearts (non-PC 44.4 +/- 7.3 vs. PC 33.5 +/- 2.6%, p = NS), although PC could salvage ischemic myocardium without Glib treatment (non-PC 49.9 +/- 5.5 vs. PC 20.0 +/- 5.6%, p < 0.05). The results suggest that K-ATP mediates PC in rabbit heart but that its role may be altered by certain anesthetic agents, The failure of Glib to prevent PC in pentobarbital-anesthetized rabbits cannot be attributed to duration of PC ischemia or myocardial O-2, demand level. The mechanism which xylazine alters the response of myocardium to the blocking effect of Glib on PC-induced cardioprotection remains to be clarified.