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Mechanisms of cardiodepression by an Na+–H+ exchange inhibitor methyl-N-isobutyl amiloride (MIA) on the heart: lack of beneficial effects in ischemia–reperfusion injury

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Although Na+–H+ exchange (NHE) inhibitors such as methyl-N-isobutyl amiloride (MIA) are known to depress the cardiac function, the mechanisms of their negative inotropic effect are not completely understood. In this study, isolated rat hearts were perfused with MIA to study its action on cardiac performance, whereas isolated subcellular organelles such as sarcolemma, myofibrils, sarcoplasmic reticulum, and mitochondria were treated with MIA to determine its effect on their function. The effect of MIA on intracellular Ca2+ mobilization was examined in fura-2-AM-loaded cardiomyocytes. MIA was observed to depress cardiac function in a concentration-dependent manner in HCO3-free buffer. On the other hand, MIA had an initial positive inotropic effect followed by a negative inotropic effect in HCO3-containing buffer. MIA increased the basal concentration of intracellular Ca2+ ([Ca2+]i) and augmented the KCl-mediated increase in [Ca2+]i. MIA did not show any direct effect on myofibrils, sarcolemma, and sarcoplasmic reticulum ATPase activities; however, this agent was found to decrease the intracellular pH, which reduced the myofibrils Ca2+-stimulated ATPase activity. MIA also increased Ca2+ uptake by mitochondria without having any direct effect on sarcoplasmic reticulum Ca2+ uptake. In addition, MIA did not protect the hearts subjected to mild Ca2+ paradox as well as ischemia–reperfusion-mediated injury. These results suggest that the increase in [Ca2+]i in cardiomyocytes may be responsible for the initial positive inotropic effect of MIA, but its negative inotropic action may be due to mitochondrial Ca2+ overloading as well as indirect depression of myofibrillar Ca2+ ATPase activity. Thus the accumulation of [H+]i as well as occurrence of intracellular and mitochondrial Ca2+ overload may explain the lack of beneficial effects of MIA in preventing the ischemia–reperfusion-induced myocardial injury.

Les inhibiteurs de l’échangeur Na+–H+ (NHE) comme le méthyl-N-isobutyl amiloride (MIA) sont connus pour diminuer la fonction cardiaque, mais les mécanismes de leur effet inotrope négatif ne sont pas totalement compris. Dans la présente étude, on a perfusé des coeurs isolés de rats avec du MIA pour examiner son action sur la performance cardiaque, et on a traité des organites subcellulaires isolés, sarcolemme, myofibrilles, réticulum sarcoplasmique et mitochondries, avec cet agent pour déterminer son effet sur leur fonction. On a examiné l’effet du MIA sur la mobilisation du Ca2+ intracellulaire dans des cardiomyocytes chargés en fura-2-AM. Le MIA a diminué la fonction cardiaque en proportion des concentrations utilisées dans le tampon sans HCO3. Par contre, le MIA a eu un effet inotrope positif initial suivi d’un effet inotrope négatif dans le tampon contenant du HCO3. Le MIA a augmenté la concentration de Ca2+ intracellulaire ([Ca2+]i) basale et amplifié l’augmentation de la [Ca2+]i induite par le KCl. Le MIA n’a pas montré d’effet direct sur les activités ATPases des MF, du SL et du RS; toutefois, cet agent a diminué le pH intracellulaire, ce qui a réduit l’activité ATPase stimulée par le Ca2+ dans les MF. Le MIA a aussi augmenté la capture de Ca2+ par les mitochondries sans avoir d’effet direct sur la capture de Ca2+ par le RS. De plus, le MIA n’a pas protégé les coeurs soumis à un léger paradoxe calcique et à une lésion d’ischémie reperfusion (I/R). Ces résultats donnent à penser que l’augmentation de la [Ca2+]i dans les cardiomyocytes pourrait être à l’origine de l’effet inotrope positif initial du MIA, mais que son action inotrope négative pourrait être due à une surcharge de Ca2+ mitochondriale et à une diminution indirecte de l’activité Ca2+-ATPase myofibrillaire. Ainsi, l’accumulation de [H+]I et la présence d’une surcharge intracellulaire et mitochondriale de Ca2+ pourrait expliquer l’absence d’effets bénéfiques du MIA pour la prévention de la lésion d’I/R myocardique.

Document Type: Research Article

Publication date: 2007-01-01

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