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(Circulation Research. 2001;88:1176.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Role of Intracellular Na⁺ Kinetics in Preconditioned Rat Heart

Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-343) and at the 65th Annual Scientific Meeting of the Japanese Circulation Society, Kyoto, Japan, March 25–27, 2001, and published in abstract form (Jpn Circ J. 2001;65[suppl 1-A]:84).

Kenichi Imahashi, Tsunehiko Nishimura, Jun Yoshioka, Hideo Kusuoka

From the Division of Tracer Kinetics (K.I., T.N., J.Y.), Osaka University Graduate School of Medicine, Suita, Osaka, and Institute for Clinical Research (H.K.), Osaka National Hospital, Osaka, Japan.

Correspondence to Hideo Kusuoka, MD, PhD, FACC, Institute for Clinical Research, Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan. E-mail kusuoka{at}onh.go.jp

Abstract

Abstract—To elucidate the role of intracellular Na⁺ kinetics in the mechanism for ischemic preconditioning (IPC), we measured intracellular Na⁺ concentration ([Na⁺]_i) using ²³Na–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 ([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 µmol/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 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 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 [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.

Key Words: ion transport • ischemia • mitochondria • nuclear magnetic resonance • reperfusion

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