Pharmacological Evidence for the Persistent Activation of ATP-Sensitive K + Channels in Early Phase of Reperfusion and Its Protective Role Against Myocardial Stunning

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Abstract
Background The activation of cardiac ATP-sensitive potassium channels is reported to protect myocardium during ischemia. However, the behavior and role of this channel during reperfusion remain uncertain. Methods and Results Guinea pig right ventricular walls were studied by use of microelectrodes and a force transducer. Each preparation was perfused 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 minutes of no-flow ischemia, which was followed by 60 minutes of reperfusion. 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 action potential amplitude (by 34.6±1.8 mV). On reperfusion, although the APD was restored, it remained shortened for up to approximately 30 minutes of reperfusion. In the presence of glibenclamide (10 μmol/L), the shortening of the APD during ischemia was significantly attenuated and the restoration of APD after reperfusion was significantly facilitated. When glibenclamide was applied from the onset of reperfusion, the persistent APD shortening was significantly suppressed. The developed tension decreased during ischemia and recovered after 60 minutes of reperfusion (up to 92.0±6.4% of preischemic values) in the untreated preparations. The application of glibenclamide that was started before 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 and 60 minutes of reperfusion were applied. This protocol produced a sustained contractile dysfunction after reperfusion (to 34.0±3.2% of preischemic values). In the presence of cromakalim (2 μmol/L), the APD shortening was enhanced during both ischemia and the early reperfusion period. Cromakalim significantly improved the contractile recovery (to 79.3±4.1% of preischemic values, P <.05 versus untreated preparations). 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 phase. The resulting shortening of the APD prevents the heart from developing myocardial stunning.