POTASSIUM CHANNEL OPENERS ATTENUATE ATRIOVENTRICULAR-BLOCK BY BUPIVACAINE IN ISOLATED HEARTS

Our purpose was to test if pinacidil and bimakalim (EMD 52692 or SR 44 866), which are ATP-sensitive K+ (K(ATP)+) channel openers, can attenu ate bupivacaine-induced atrioventricular (AV) block. Bupivacaine-induc ed AV block was studied in 24 isolated guinea pig hearts with or witho ut either pinacidil or bimakalim. Hearts were perfused at 55 mm Hg wit h a modified Krebs' perfusate. Variables monitored were: heart rate, A V conduction time, left ventricular pressure, coronary flow, and myoca rdial oxygen extraction. Bupivacaine was infused at a constant concent ration of 4 muM to induce first degree AV block and 15-25 muM to induc e second degree heart block. During a stable AV block (e.g., first deg ree, 2:1, 3:2, or 4:3), K+ channel openers, pinacidil (up to 30 muM) o r bimakalim (up to 2 muM) were added to perfusate containing bupivacai ne. The effects of K+ channel openers were also examined in the presen ce of the selective K(ATP)+ channel blocker, glibenclamide (2.2 muM). On the average, 4 muM bupivacaine prolonged AV conduction by 53%, and decreased heart rate by 13%, left ventricular pressure by 26%, coronar y flow by 6%, and percent oxygen extraction by 7%. In the presence of bupivacaine, pinacidil and bimakalim additionally decreased left ventr icular pressure and oxygen extraction, markedly increased coronary flo w, and attenuated the prolongation of AV conduction by 20% with no fur ther change in heart rate. The beneficial effect of bimakalim on AV bl ock was reversed by glibenclamide. Second degree AV block produced by higher doses of bupivacaine was converted to first degree AV block by either pinacidil or bimakalim in 6 of 8 and 7 of 8 hearts, respectivel y The addition of glibenclamide reversed the beneficial effect of bima kalim so that second degree AV block reoccurred in all hearts. These r esults indicate that administration of K(ATP)+ channel openers may ame liorate the AV blocking effect of bupivacaine and thereby reduce one o f its cardiac toxic effects.