Reduction by SEA0400 of myocardial ischemia-induced cytoplasmic and mitochondrial Ca2+ overload

Namekata, Iyuki; Shimada, Hideaki; Kawanishi, Toru; Tanaka, Hikaru; Shigenobu, Koki

doi:10.1016/j.ejphar.2006.06.012

Cited by 35 publications

(40 citation statements)

References 36 publications

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“…Data acquisition and analysis were performed with the aquacosmos system (Hamamatsu Photonics, Hamamatsu). Calibration was performed in situ as in our previous study (17).…”

Section: +mentioning

confidence: 99%

Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

et al. 2007

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Abstract. Involvement of the Na + / Ca 2+ exchanger in ouabain-induced inotropy and arrhythmogenesis was examined with a specific inhibitor, SEA0400. In right ventricular papillary muscle isolated from guinea-pig ventricle, 1 µM SEA0400, which specifically inhibits the Naexchanger by 80%, reduced the ouabain (1 µM)-induced positive inotropy by 40%, but had no effect on the inotropy induced by 100 µM isobutyl methylxantine. SEA0400 significantly inhibited the contracture induced by low Na + solution. In HEK293 cells expressing the Naexchanger, 1 µM ouabain induced an increase in intracellular Ca 2+, which was inhibited by SEA0400. The arrhythmic contractions induced by 3 µM ouabain were significantly reduced by SEA0400. These results provide pharmacological evidence that the Na2+ exchanger is involved in ouabain-induced inotropy and arrhythmogenesis.

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“…Data acquisition and analysis were performed with the aquacosmos system (Hamamatsu Photonics, Hamamatsu). Calibration was performed in situ as in our previous study (17).…”

Section: +mentioning

confidence: 99%

Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

et al. 2007

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“…6) SEA0400 attenuated cytoplasmic and mitochondrial Ca 2+ overload and preserved tissue ATP content and mitochondrial membrane potential during ischemia. 7) These results suggested that inhibition of plasmalemmal NCX protects the mitochondria through attenuation of Ca 2+ overload during myocardial ischemia. However, the following issues relevant to this hypothesis have not yet been clarified.…”

mentioning

confidence: 72%

“…These results indicate that the decrease in mitochondrial membrane potential could be the result but not the cause of rise in mitochondrial Ca 2+ concentration. Thus, the preservation of the mitochondrial membrane potential in ischemic cardiomyocytes by SEA0400 7) could be attributed to the attenuation of the rise in mitochondrial Ca 2+ concentration. Concerning the mechanisms for mitochondrial Ca 2+ regulation (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Fluorescence Analysis of the Mitochondrial Effect of a Plasmalemmal Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, SEA0400, in Permeabilized H9c2 Cardiomyocytes

Namekata

Hamaguchi

Iida-Tanaka

et al. 2017

Biological & Pharmaceutical Bulletin

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The Na + -Ca 2+ exchanger (NCX) is involved in the regulation of Ca 2+ concentration in the myocardium. The plasmalemmal NCX basically functions in the forward (transplasmalemmal Ca 2+ efflux) mode, but under pathological conditions such as ischemia, it is postulated to function in the reverse (Ca 2+ influx) mode and contribute to cellular damage. 1) SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline) is a selective inhibitor of NCX with minimum effects on other plasmalemmal transporters and ion channels, [2][3][4][5] and thus have been used as a potent pharmacological tool in NCX research. We have previously examined the effects of SEA0400 on a coronary-perfused myocardial ischemia-reperfusion model and found that SEA0400 enhances the recovery of contractile force and action potential duration after reperfusion. 6) SEA0400 attenuated cytoplasmic and mitochondrial Ca 2+ overload and preserved tissue ATP content and mitochondrial membrane potential during ischemia. 7) These results suggested that inhibition of plasmalemmal NCX protects the mitochondria through attenuation of Ca 2+ overload during myocardial ischemia. However, the following issues relevant to this hypothesis have not yet been clarified. Firstly, can the attenuation of the rise in mitochondrial Ca 2+ be attributed to the attenuation of the rise in cytoplasmic Ca 2+ by SEA0400? Secondly, can the preservation of the mitochondrial membrane potential be attributed to the attenuation of the rise in mitochondrial Ca 2+ by SEA0400? Thirdly, does SEA0400 have any direct effect on mitochondrial Ca 2+ transport pathways including the mitochondrial NCX, which has been considered to have pivotal roles in intracellular Ca 2+ handling? 8) In the present study, to obtain information to answer these questions, we constructed a fluorescence-based system for the analysis of mitochondrial Ca 2+ concentration. We used the rat embryonic heart derived H9c2 cells expressing the mitochondria-targeted yellow cameleon 3.1, a protein Ca 2+ indicator based on fluorescence resonance energy transfer (FRET) between cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP). 9) After permeabilizing the cells with digitonin, the extramitochondrial environment could be manipulated by changing the cell perfusate and the resulting changes in mitochondrial Ca 2+ concentration monitored with yellow cameleon fluorescence ratio. We studied the regulation of mitochondrial Ca 2+ under normal and ischemic condition, and examined the effect of pharmacological agents including SEA0400.

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“…Some agents such as Cl − -channel blockers (34) and Na + /Ca 2+ -exchanger inhibitors (35) showed protection against myocardial ischemiareperfusion injury with no evidence of cardiosupression. Evidence available at present suggests that preservation of mitochondrial function is involved in the protective effect of these agents (36). Various ion channels and transporters are present on the mitochondrial membrane and their modulation has been reported to affect mitochondrial function (37).…”

Section: Effects Of Ischemiamentioning

confidence: 99%

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

et al. 2009

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Abstract. The waveform of the myocardial action potential (AP) triggering contraction differs among the species, developmental stage, and pathological state. The species difference in heart rate, which inversely correlates with body size, originates in the ion-channel mechanisms responsible for diastolic depolarization of the sinoatrial node. In some cases, such as the chronically AV-blocked dog and 11-to 13-day chick embryo, the repolarization reserve is decreased making the heart useful for drug evaluation. The degree of dependence of contraction on sarcoplasmic reticulum (SR) function increases during development. The large SR dependence and short AP of the adult mouse and rat support their rapid contraction under high heart rate. The function of the Na + /Ca 2+ exchanger is affected by AP waveform and ion concentrations; its major role is Ca 2+ extrusion, but under pathological conditions such as ischemia-reperfusion, it allows Ca 2+ influx and leads to myocardial injury, including loss of mitochondrial function. The role of mitochondria in ATP supply is less in the fetus where glycolysis plays a greater role. The pharmacological properties of the myocardium are affected by all of these factors and also by autonomic innervation and the hormonal status. Such comprehensive understanding is indispensable for the development of novel therapeutic strategies.

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Reduction by SEA0400 of myocardial ischemia-induced cytoplasmic and mitochondrial Ca2+ overload

Cited by 35 publications

References 36 publications

Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

Involvement of the Na+/Ca2+ Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

Fluorescence Analysis of the Mitochondrial Effect of a Plasmalemmal Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Inhibitor, SEA0400, in Permeabilized H9c2 Cardiomyocytes

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

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