Received for publication November 24, 2004.
Revised December 21, 2004.
Accepted for publication January 5, 2005.

Pretreatment with pinacidil promotes arrhythmias in an isolated tissue model of cardiac ischemia and reperfusion

Abstract

It is not clear whether activation of ATP-sensitive potassium channels (K_ATP) with pinacidil in advance of ischemia and reperfusion promotes or suppresses arrhythmias. This study determines the effects of pinacidil pretreatment on arrhythmias and changes in cellular electrophysiological parameters in segments of guinea pig right ventricular free walls exposed to simulated ischemia and reperfusion. Microelectrode recordings were made from endo- and epicardium during endocardial pacing. Preparations were superfused with Tyrode's solution, and then exposed for 5 min to either 100 micromolar pinacidil or its solvent. After a 5 min washout, preparations were exposed to 15 min of ischemic conditions (hypoxia, hypercapnia, hyperkalemia, acidosis, lactate accumulation, glucose-free) followed by reperfusion with Tyrode's solution. Pinacidil pretreatment increased ischemia-induced abbreviation of endo- and epicardial action potential durations and effective refractory periods. Pinacidil had no effect on endocardial conduction times, but greatly prolonged transmural conduction during ischemia and early reperfusion, and increased the incidence of transmural conduction block. Pinacidil pretreatment caused a significant increase in the incidence of arrhythmias in ischemia and reperfusion. Reperfusion arrhythmias in control preparations had electrophysiological characteristics of activity initiated by afterpotentials. However, arrhythmias with these characteristics were absent in pinacidil pretreated preparations, and all reperfusion arrhythmias exhibited characteristics of reentry. The increased incidence of reentrant arrhythmias is likely explained by pinacidil-induced reduction in effective refractory periods in combination with prolonged transmural conduction times. Thus, pinacidil pretreatment enhanced the effects of ischemia and reperfusion on action potential duration, effective refractory period and transmural conduction, and promoted reentrant arrhythmias.

Key words: ATP-senstive potassium channel, delayed afterdepolarization, heart, oscillatory afterpotential, preconditioning, reentry

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