Modulation of late sodium current by Ca2+–calmodulin‐dependent protein kinase II, protein kinase C and Ca2+ during hypoxia in rabbit ventricular myocytes
New Findings What is the central question of this study? Hypoxia‐induced increase in late sodium current (INa,L) is associated with conditions causing cellular Ca2+ overload and contributes to arrhythmogenesis in the ventricular myocardium. The INa,L is an important drug target. We investigated intr...
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Veröffentlicht in: | Experimental physiology 2017-07, Vol.102 (7), p.818-834 |
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Sprache: | eng |
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Zusammenfassung: | New Findings
What is the central question of this study?
Hypoxia‐induced increase in late sodium current (INa,L) is associated with conditions causing cellular Ca2+ overload and contributes to arrhythmogenesis in the ventricular myocardium. The INa,L is an important drug target. We investigated intracellular signal transduction pathways involved in modulation of INa,L during hypoxia.
What is the main finding and its importance?
Hypoxia caused increases in INa,L, reverse Na+–Ca2+ exchange current and diastolic [Ca2+], which were attenuated by inhibitors of Ca2+–calmodulin‐dependent protein kinase II (CaMKII) and protein kinase C and by a Ca2+ chelator. The findings suggest that CaMKII, protein kinase C and Ca2+ all participate in mediation of the effect of hypoxia to increase INa,L.
Hypoxia leads to augmentation of the late sodium current (INa,L) and cellular Na+ loading, increased reverse Na+–Ca2+ exchange current (reverse INCX) and intracellular Ca2+ loading in rabbit ventricular myocytes. The purpose of this study was to determine the intracellular signal transduction pathways involved in the modulation of INa,L during hypoxia in ventricular myocytes. Whole‐cell and cell‐attached patch‐clamp techniques were used to record INa,L, and the whole‐cell mode was also used to record reverse INCX and to study intercellular signal transduction mechanisms that mediate the increased INa,L. Dual excitation fluorescence photomultiplier systems were used to record the calcium transient in ventricular myocytes. Hypoxia caused increases of INa,L and reverse INCX. These increases were attenuated by KN‐93 (an inhibitor of Ca2+–calmodulin‐dependent protein kinase II), bisindolylmaleimide VI (BIM; an inhibitor of protein kinase C) and BAPTA AM (a Ca2+ chelator). KN‐93, BIM and BAPTA AM had no effect on INa,L in normoxia. In studies of KN‐93, hypoxia alone increased the density of INa,L from −0.31 ± 0.02 to −0.66 ± 0.03 pA pF−1 (n = 6, P |
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ISSN: | 0958-0670 1469-445X |
DOI: | 10.1113/EP085990 |