Open AccessInhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions
Author(s) -
XiaoHong Wei,
Shandong Yu,
Lu Ren,
Shiyuan Huang,
Qing Yang,
Ping Wang,
Yanpeng Chu,
Wei Yang,
Ye Ding,
Yong Huo,
Lin Wu
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-01056-0
Subject(s) - calcium , medicine , contraction (grammar) , repolarization , calcium in biology , sodium , intracellular , endocrinology , chemistry , pharmacology , cardiology , electrophysiology , biochemistry , organic chemistry
Cardiac arrhythmias associated with intracellular calcium inhomeostasis are refractory to antiarrhythmic therapy. We hypothesized that late sodium current ( I Na ) contributed to the calcium-related arrhythmias. Monophasic action potential duration at 90% completion of repolarization (MAPD 90 ) was significantly increased and ventricular arrhythmias were observed in hearts with increased intracellular calcium concentration ([Ca 2+ ] i ) by using Bay K 8644, and the increase became greater in hearts treated with a combination of ATX-II and Bay K 8644 compared to Bay K 8644 alone. The prolongations caused by Bay K 8644 and frequent episodes of ventricular tachycardias, both in absence and presence of ATX-II, were significantly attenuated or abolished by late I Na inhibitors TTX and eleclazine. In rabbit ventricular myocytes, Bay K 8644 increased I CaL density, calcium transient and myocyte contraction. TTX and eleclazine decreased the amplitude of late I Na , the reverse use dependence of MAPD 90 at slower heart rate, and attenuated the increase of intracellular calcium transient and myocyte contraction. TTX diminished the phosphorylation of CaMKII-δ and Na v 1.5 in hearts treated with Bay K 8644 and ATX-II. In conclusion, late I Na contributes to ventricular arrhythmias and its inhibition is plausible to treat arrhythmias in hearts with increased [Ca 2+ ] i