Abstract
We examined the intracellular mechanisms for endothelin-1-induced positive and negative inotropic components that coexist in the mouse ventricular myocardium using isolated ventricular tissue and myocytes from 4-week-old mice. In the presence of SEA0400, a specific inhibitor of the Na+–Ca2+ exchanger, endothelin-1 produced positive inotropy. Endothelin-1, when applied to cardiomyocytes in the presence of SEA0400, did not change the peak amplitude of the Ca2+ transient but increased intracellular pH and Ca2+ sensitivity of contractile proteins. On the other hand, in the presence of dimethylamiloride (DMA), a specific inhibitor of the Na+–H+ exchanger, endothelin-1 produced negative inotropy. In cardiomyocytes, in the presence of DMA, endothelin-1 produced a decrease in peak amplitude of the Ca2+ transient. In the presence of both DMA and SEA0400, endothelin-1 produced neither positive nor negative inotropy. Positive inotropy was blocked by BQ-123 and negative inotropy by BQ-788. These results suggested that endothelin-1-induced positive inotropy is mediated by ETA receptors, activation of the Na+–H+ exchanger and an increase in intracellular pH and Ca2+ sensitivity and that the negative inotropy is mediated by ETB receptors, activation of the Na+–Ca2+ exchanger and decrease in Ca2+ transient amplitude.
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This study was partly performed as a part of the project Research on the Molecular Mechanisms of Appearance of Age-related Diseases by Failure of Cell Function Control System, and their Prevention and Treatment by the Research Center for Aging and Age-related Diseases established in the Toho University Faculty of Pharmaceutical Sciences.
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Namekata, I., Fujiki, S., Kawakami, Y. et al. Intracellular mechanisms and receptor types for endothelin-1-induced positive and negative inotropy in mouse ventricular myocardium. Naunyn-Schmied Arch Pharmacol 376, 385–395 (2008). https://doi.org/10.1007/s00210-007-0228-9
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DOI: https://doi.org/10.1007/s00210-007-0228-9