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 (23)Na-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 IPC. The mitochondrial ATP-sensitive K(+) (mito K(ATP)) channel activator diazoxide (30 micromol/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 micromol/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 micromol/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 mito K(ATP) channel activation mainly contributes to functional protection in IPC hearts. The contribution of mito K(ATP) channel-independent pathway relating to Na(+) kinetics including reduced Na(+) influx is limited in functional protection of IPC.
Imahashi
K
K
Division of Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Nishimura
T
T
Yoshioka
J
J
Kusuoka
H
H
D000818:Animals; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D015221:Potassium Channels; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000032:analysis / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D003652:Decanoic Acids; D006880:Hydroxy Acids; D008565:Membrane Proteins; D015221:Potassium Channels; D017923:Sodium-Hydrogen Exchangers; C117780:mitochondrial K(ATP) channel; D010042:Ouabain; C052853:5-hydroxydecanoic acid; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D003981:Diazoxide