Coordinate interaction between ATP-sensitive K+ channel and Na+,K+-ATPase modulates ischemic preconditioning

Background-We reported that digoxin abolishes the infarct size (IS)-limitin g effect of ischemic preconditioning (IPC). Because ATP-sensitive K+ (K-ATP ) channels are involved in IPC, we studied whether Na+,K+-ATPase and K-ATP channels functionally interact, thereby modulating IPC. Methods and Results-Rabbits received 30 minutes of coronary artery occlusio n followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occl usion followed by 10 minutes of reperfusion. The IS, expressed as a percent age of the area at risk, was 40.2+/-2.8% in control and 39.8+/-5.0% in digo xin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a K-AT P channel opener, reduced IS to 11.8+/-1.8% and 13.4+/-2.6% (P<0.05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5+/-3.3% ), whereas it did not change that induced by cromakalim (18.8+/-3.0%). In p atch-clamp experiments, digoxin was found to inhibit the opening of K-ATP c hannels in single ventricular myocytes in which ATP depletion had been indu ced by metabolic stress. In contrast, digoxin had little effect on the chan nel opening induced by cromakalim. Moreover, the inhibitory action of digox in on channel activities was dependent on subsarcolemmal ATP concentration. Conclusions-The IS-limiting effect of IPC is modulated by an interaction be tween K-ATP channels and Na+,K+-ATPase through subsarcolemmal ATP.