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Na⁺/H⁺ exchanger inhibitor cariporide attenuates the mitochondrial Ca²⁺ overload and PTP opening

¹Department of Pediatrics, Yamanashi University School of Medicine, Yamanashi; and ²Department of Physiology, Tokai University School of Medicine, Kanagawa, Japan

Submitted 11 May 2006 ; accepted in final form 18 August 2007

The Na⁺/H⁺ exchanger (NHE) inhibitor cariporide has a cardioprotective effect in various animal models of myocardial ischemia-reperfusion. Recent studies have suggested that cariporide interacts with mitochondrial Ca²⁺ overload and the mitochondrial permeability transition (MPT); however, the precise mechanisms remain unclear. Therefore, we examined whether cariporide affects mitochondrial Ca²⁺ overload and MPT. Isolated adult rat ventricular myocytes were used to study the effects of cariporide on hypercontracture induced by ouabain or phenylarsine oxide (PAO). Mitochondrial Ca²⁺ concentration ([Ca²⁺]_m) and the mitochondrial membrane potential (_m) were measured by loading myocytes with rhod-2 and JC-1, respectively. We also examined the effect of cariporide on the MPT using tetramethylrhodamine methyl ester (TMRM) and oxidative stress generated by laser illumination. Cariporide (1 µM) prevented ouabain-induced hypercontracture (from 40 ± 2 to 24 ± 2%, P < 0.05) and significantly attenuated ouabain-induced [Ca²⁺]_m overload (from 149 ± 6 to 121 ± 5% of the baseline value, P < 0.05) but did not affect _m. These results indicate that cariporide attenuates the [Ca²⁺]_m overload without the accompanying depolarization of _m. Moreover, cariporide increased the time taken to induce the MPT (from 79 ± 11 to 137 ± 20 s, P < 0.05) and also attenuated PAO-induced hypercontracture (from 59 ± 3 to 50 ± 4%, P < 0.05). Our data indicate that cariporide attenuates [Ca²⁺]_m overload and MPT. Thus these effects might potentially contribute to the mechanisms of cardioprotection afforded by NHE inhibitors.

calcium; mitochondria; Na⁺/H⁺ exchange; permeability transition pore; adenosine 5'-triphosphate potassium channel

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