Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions

Xiao-Hong Wei,Si-Hui Huang,Yan-Peng Chu,Qiao-Mei Yang,Lu Ren,Yong Huo,Shan-Dong Yu,Ping Wang,Lin Wu,Wei Yang,Yan-Sheng Ding

doi:10.1038/s41598-017-01056-0

Abstract

Cardiac arrhythmias associated with intracellular calcium inhomeostasis are refractory to antiarrhythmic therapy. We hypothesized that late sodium current (INa) contributed to the calcium-related arrhythmias. Monophasic action potential duration at 90% completion of repolarization (MAPD90) was significantly increased and ventricular arrhythmias were observed in hearts with increased intracellular calcium concentration ([Ca2+]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 INa inhibitors TTX and eleclazine. In rabbit ventricular myocytes, Bay K 8644 increased ICaL density, calcium transient and myocyte contraction. TTX and eleclazine decreased the amplitude of late INa, the reverse use dependence of MAPD90 at slower heart rate, and attenuated the increase of intracellular calcium transient and myocyte contraction. TTX diminished the phosphorylation of CaMKII-δ and Nav 1.5 in hearts treated with Bay K 8644 and ATX-II. In conclusion, late INa contributes to ventricular arrhythmias and its inhibition is plausible to treat arrhythmias in hearts with increased [Ca2+]i

Highlights

(MAPD90) was significantly increased and ventricular arrhythmias were observed in hearts with increased intracellular calcium concentration ([Ca2+]i) by using Bay K 8644, and the increase became greater in hearts treated with a combination of anemone toxin (ATX)-II and Bay K 8644 compared to Bay K 8644 alone
Late INa was increased in cardiomyocytes when [Ca2+]i was high via the subsequent activation of Ca2+/calmodulin dependent protein kinase (CaMK)II and protein kinase C (PKC) pathways, and the resulting increase in intracellular sodium concentration would further elevate [Ca2+]i via reversed sodium-calcium exchange[15]
In the continuous presence of 3 nM ATX-II, Bay K 8644 (10–200 nM) prolonged MAPD90 in concentration-dependent manners, and the increase of both epi- and endo- MAPD90 by Bay K 8644 (200 nM) were significantly greater in hearts treated with a combination of 3 nM ATX-II, than that in hearts treated with Bay K 8644 alone

Summary

Introduction

(MAPD90) was significantly increased and ventricular arrhythmias were observed in hearts with increased intracellular calcium concentration ([Ca2+]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. Recent clinical reports indicate that the late sodium current (late INa) inhibitors ranolazine and mexiletine are effective, at least in part, in preventing or treating increased [Ca2+]i-associated cardiac arrhythmias, including LQTs 8 and myocardial hypertrophy[10, 11], etc The mechanisms underlying these treatments remain to be investigated. Late INa was increased in cardiomyocytes when [Ca2+]i was high via the subsequent activation of Ca2+/calmodulin dependent protein kinase (CaMK)II and protein kinase C (PKC) pathways, and the resulting increase in intracellular sodium concentration would further elevate [Ca2+]i via reversed sodium-calcium exchange[15] This positive vicious cycle may enhance the proarrhythmic characteristics of increased [Ca2+]i in the heart. Arrows indicate ventricular tachycardia (VT) occurred at or above the concentration indicated

Methods

Results

Conclusion