Mechanistic distinction between activation and inhibition of (Na+K)-ATPase-mediated Ca influx in cardiomyocytes |
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Authors: | Kai Y. Xu Weizhong Zhu Ling Chen Christopher DeFilippi Jin Zhang Rui-Ping Xiao |
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Affiliation: | aDepartment of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA;bLaboratory of Cardiovascular Science, National Institute on Aging, Baltimore, MD 21224, USA;cDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;dDepartment of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA |
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Abstract: | (Na++K+)-ATPase (NKA) mediates positive inotropy in the heart. Extensive studies have demonstrated that the reverse-mode Na+/Ca2+-exchanger (NCX) plays a critical role in increasing intracellular Ca2+ concentration through the inhibition of NKA-induced positive inotropy by cardiac glycosides. Little is known about the nature of the NCX functional mode in the activation of NKA-induced positive inotropy. Here, we examined the effect of an NKA activator SSA412 antibody on 45Ca influx in isolated rat myocytes and found that KB-R7943, a NCX reverse-mode inhibitor, fails to inhibit the activation of NKA-induced 45Ca influx, suggesting that the Ca2+ influx via the reverse-mode NCX does not mediate this process. Nifedipine, an L-type Ca2+ channel (LTCC) inhibitor, completely blocks the activation of NKA-induced 45Ca influx, suggesting that the LTCC is responsible for the moderate increase in intracellular Ca2+. In contrast, the inhibition of NKA by ouabain induces 4.7-fold 45Ca influx compared with the condition of activation of NKA. Moreover, approximately 70% of ouabain-induced 45Ca influx was obstructed by KB-R7943 and only 30% was impeded by nifedipine, indicating that both the LTCC and the NCX contribute to the rise in intracellular Ca2+ and that the NCX reverse-mode is the major source for the 45Ca influx induced by the inhibition of NKA. This study provides direct evidence to demonstrate that the activation of NKA-induced Ca2+ increase is independent of the reverse-mode NCX and pinpoints a mechanistic distinction between the activation and inhibition of the NKA-mediated Ca2+ influx path ways in cardiomyocytes. |
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Keywords: | (Na++K+)-ATPase Na+/Ca2+-exchanger Ca2+ influx Allosteric activator Digitalis drugs |
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