PHARMACOLOGICAL EVIDENCE FOR THE PERSISTENT ACTIVATION OF ATP-SENSITIVE K+ CHANNELS IN EARLY PHASE OF REPERFUSION AND ITS PROTECTIVE ROLE AGAINST MYOCARDIAL STUNNING

Background The activation of cardiac ATP-sensitive potassium channels is reported to protect myocardium during ischemia. However, the behavi or and role of this channel during reperfusion remain uncertain. Metho ds and Results Guinea pig right ventricular walls were studied by use of microelectrodes and a force transducer. Each preparation was perfus ed via the coronary artery at a constant flow rate and was stimulated at 3 Hz. In the first protocol, the preparation was subjected to 10 mi nutes of no-flow ischemia, which was followed by 60 minutes of reperfu sion. Introduction of ischemia shortened the action potential duration (APD) to 58.7+/-3.1% of the preischemic values, in association with a decrease in the resting membrane potential (by 12+/-0.8 mV) and actio n potential amplitude (by 34.6+/-1.8 mV). On reperfusion, although the APD was restored, it remained shortened for up to approximately 30 mi nutes of reperfusion, In the presence of glibenclamide (10 mu mol/L), the shortening of the APD during ischemia was significantly attenuated and the restoration of APD after reperfusion was significantly facili rated. When glibenclamide was applied from the onset of reperfusion, the persistent APD shortening was significantly suppressed. The develo ped tension decreased during ischemia and recovered after 60 minutes o f reperfusion (up to 92.0+/-6.4% of preischemic values) in the untreat ed preparations. The application of glibenclamide that was started bef ore ischemia or from the onset of reperfusion significantly suppressed the recovery of contractility (P<.05 versus untreated preparations). In the second series of experiments, 20 minutes of no-flow ischemia an d 60 minutes of reperfusion were applied. This protocol produced a sus tained contractile dysfunction after reperfusion (to 34.0+/-3.2% of pr eischemic values). In the presence of cromakalim (2 mu mol/L), the APD shortening was enhanced during both ischemia and the early reperfusio n period. Cromakalim significantly improved the contractile recovery ( to 79.3+/-4.1% of preischemic values, P<.05 versus untreated preparati ons). The application of cromakalim that was started from the onset of reperfusion also improved the contractile recovery during this phase and this effect was associated with enhanced APD shortening. However, the cromakalim-treated preparations demonstrated a higher incidence of ventricular fibrillation during reperfusion. Conclusions Cardiac ATP- sensitive potassium channels are activated by ischemia, and a fraction of these channels remains activated during the early reperfusion phas e. The resulting shortening of the APD prevents the heart from develop ing myocardial stunning.