To elucidate the role of intracellular Na+ kinetics in the mechanism for ischemic preconditioning (IPC), we measured intracellular Na+ concentration ([Na+]i) using 23Na-magnenc 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 (Δ[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 IPC. The mitochondrial ATP-sensitive K+ (mito KATP) channel activator diazoxide (30 μmol/L) completely mimicked both [Na+]i kinetics and functional recovery in IPC without any additive effects to IPC. The mito KATP channel blocker 5-hydroxydecanoic acid (100 μmol/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 μmol/L) did not change d[Na+]i/dt in non-IPC hearts, but it abolished the IPCor 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 Δ[Na+]i than other ouabain groups. In conclusion, alteration of Na+ kinetics by preserving Na+ efflux via Na+/K+-ATPase mediated by mito KATP channel activation mainly contributes to functional protection in IPC hearts. The contribution of mito KATP channel-independent pathway relating to Na+ kinetics including reduced Na+ influx is limited in functional protection of IPC.
- Ion transport
- Nuclear magnetic resonance
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine