Role of intracellular Na+ kinetics in preconditioned rat heart

To elucidate the role of intracellular Na+ kinetics in the mechanism for ischemic preconditioning (IPC), we measured intracellular Na+ concentration ([Na+](i)) using Na-23-magnetic resonance spectroscopy in isolated rat hearts. IPC significantly delayed the initial [Na+](i) increase (d[Na+](i)/dt) compared with non-IPC control, resulting in attenuation of Na+ accumulation (Delta [Na+](i)) during 27 minutes of ischemia with better functional recovery. [Na+](i) in IPC, but not in control, recovered to preischemic level during a 6-minute reperfusion. The Na+-H+ exchange inhibitor further suppressed d[Na+](i)/dt in both control and IPC hearts with concomitant improvement of functional recovery, suggesting little contribution to the mechanism of LPC. The mitochondrial ATP-sensitive K+ (mito K-ATP) channel activator diazoxide (30 mu mol/L) completely mimicked both [Na+](i) kinetics and functional recovery in IPC without any additive effects to IPC. The mito K-ATP channel blocker 5-hydroxydecanoic acid (100 mu mol/L) lost protective effect as well as the attenuation of d[Na+](i)/dt and [Na+](i) recovery induced by diazoxide, However, 5-hydroxydecanoic acid also lost IPC-induced protection, but incompletely abolished the alteration of d[Na+](i)/dt and the [Na+](i) recovery. The Na+/K+-ATPase inhibitor ouabain (200 mu mol/L) did not change d[Na+](i)/dt in non-IPC hearts, but it abolished the IPC- or diazoxide-induced reduction of d[Na+](i)/dt and the [Na+](i) recovery, whereas IPC followed by ouabain treatment showed partial functional recovery with smaller Delta [Na+](i) than other ouabain groups. In conclusion, alteration of Na+ kinetics by preserving Na+ efflux via Na+/K+-ATPase mediated by mite K-ATP channel activation mainly contributes to functional protection in LPC hearts. The contribution of mite K-ATP channel-independent pathway relating to Na+ kinetics including reduced Na+ influx is limited in functional protection of IPC.