Preconditioning is not abolished by the delayed rectifier K+ blocker dofetilide

Abstract

ATP-sensitive potassium channels are thought to play an important role in preconditioning. possibly due to shortening of the action potential duration (APD). The purpose of this study was to determine the effect of the class III antiarrhythmic agent dofetilide on preconditioning at a dose that abolishes APD shortening during ischemia A pilot study was performed to find a dose of dofetilide that would abolish the APD shortening effect of preconditioning Anesthetized dogs were subjected to 5-min coronary occlusion (or sham) and 10-min reperfusion followed by 60-min coronary occlusion. Monophasic action potentials were recorded periodically throughout the experiment. Significant APD shortening was observed during the 5- and 60-min ischemic periods, although preconditioning did not further enhance APD shortening during the prolonged ischemia. Dofetilide (1 mg/kg + 0.01 mg.kg-1.h-1 iv) abolished the APD shortening effect of ischemia. The effect of this dose of dofetilide on the protective action of preconditioning was then determined. Preconditioning significantly reduced infarct size expressed as a percentage of the area at risk compared with nonpreconditioned hearts. Dofetilide had no effect on infarct size when given to nonpreconditioned hearts. In addition, dofetilide did not alter the protective effect of preconditioning. No differences in collateral blood flow during ischemia were observed for any group. This study shows that the class III antiarrhythmic agent dofetilide does not abolish preconditioning and that the cardioprotective effect of preconditioning is independent of APD shortening below baseline values.

Mitochondrial K channels in cell survival and death

“…Similar lack of correlation between the extent of action potential shortening and the reduction of infarct size has also been shown with cromakalim and BMS-180448 [9,10]. Furthermore, Grover et al [11] showed that prevention of action potential shortening by concomitant treatment of dofetilide did not reverse cardioprotective effects of cromakalim. These studies suggested that the opening of the surface KATP channel may not be necessary for the cardioprotection induced in IPC.…”

Dofetilide

“…26 I K(ATP) channels are thought to play a role in ischemic preconditioning and, interestingly, indirect reversal of the electromechanical effects of stimulation of I K(ATP) channels by dofetilide does not diminish ischemic preconditioning. 27,28 Dofetilide-induced action potential prolongation is blocked by ␤-adrenergic stimulation. 29 This results from adrenergic enhancement of I Ks , which shortens action potential duration.…”

From the S.P. Botkin’s idea of “preexposure” to preconditioning phenomenon. Perspectives for use of phenomena of ischemic and pharmacological preconditioning

“…В настоящее время преобладает мнение, что тран-зиторные ишемические атаки являются прежде все-го фактором риска мозгового инсульта. Упоминания об их саногенном эффекте в публикациях последних лет встречаются довольно редко [55][56][57][58][59].…”

“…Первоначально ответственными за ИП рассматривались сарколем-мные каналы Katp, активация которых сокращает продолжительность потенциала действия, ингиби-рует поток кальция через каналы L-типа, в резуль-тате чего уменьшается внутриклеточная перегрузка кальцием в процессе ишемии [56,59]. Позднее было установлено, что укорочение потенциала действия активацией сарколемных Katp-каналов не суще-ственно для индуцированной противоишемической защиты миокарда, а при активации митохондри-альных Katp-каналов воспроизводится эффект ИП [56,57]. В последнее время показано, что активация Katp-каналов внутренней митохондриальной мем-браны является не только необходимым, но и до-статочным условием для реализации защитного эффекта гипоксического и ишемического прекон-диционирования [35].…”