Role of cardiac ATP-sensitive K^+ channels clarified by Kir6.2-deficient mice

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In order to clarify the pathophysioloical significance of sarcolemmal ATP-sensitive K^+ (K_<ATP>) channel in cardiac cells, we conducted functional experiments using Kir6.2-deficient (Kir6.2^<-/->) mice. In open cell-attached patches of ventricular cells of wild type (Kir6.2^<+/+>) but not of Kir6.2^<-/-> mice, single K_<ATP> channel activity with the slope conductance of about 80 pS could be recorded during exposure to an internal solution containing a trace amount of ATP.The ATP-sensitive K^+ current was activated by K^+ channel openers (KCOs) such as pinacidil and cromakalim and the exposure to a glucose-free, dinitrophenol-containing solution in Kir6.2^<+/+> ventricular cells but not in Kir6.2^<-/-> cells. The action potential duration (APD) of Kir6.2^<+/+> ventricular cells but not of Kir6.2^<-/-> cells was shortened by KCOs and metabolic blockade. In anesthetized Kir6.2^<+/+> and Kir6.2^<-/-> mice, coronary artery was occluded for 45 min and reperfused for 120 min, and the infarc … More t size was evaluated by triphenyl tetrazolium chloride staining. For ischemic preconditioning (IP) experiments coronary artery was occluded for three periods of 3 min, each followed by 5 min reperfusion, before the long-term ischemia. IP reduced the infarct size in Kir6.2^<+/+> mice but not in Kir6.2^<-/-> mice. The hearts were removed from Kir6.2^<+/+> and Kir6.2^<-/-> mice, and retrogradely perfused with a physiological solution. Left ventricular pressure was measured using a water-filled balloon inserted into the left ventricle. Global ischemia was produced by stopping the perfusion for 15 min, and then the heart was reperfused for 30 min. During ischemia an increase in the left ventricular end-diastolic pressure was more marked and more rapid in Kir6.2^<-/-> hearts, compared to Kir6.2^<+/+> hearts. The recovery of the left ventricular contractile function during reperfusion was worse in Kir6.2^<-/-> hearts than in Kir6.2^<+/+> hearts. These findings indicate that Kir6.2 is essential for the action potential shortening during the exposure to the metabolic blockade and KCOs. In addition, sarcolemmal K_<ATP> channel is important for the establishment if ischemic preconditioning and the maintenace of mechanical function during ischemia and reperfusion. Less