Curcumin, a Multi-Ion Channel Blocker That Preferentially Blocks Late Na+ Current and Prevents I/R-Induced Arrhythmias

Lv Song,Pei-Pei Zhang,Ze-Fu Zhang,Zhi-Pei Liu,Pei-Hua Zhang,Zhen-Zhen Cao,Liang-Kun Hu,Ji-Hua Ma

doi:10.3389/fphys.2020.00978

Abstract

Increasing evidence shows that Curcumin (Cur) has a protective effect against cardiovascular diseases. However, the role of Cur in the electrophysiology of cardiomyocytes is currently not entirely understood. Therefore, the present study was conducted to investigate the effects of Cur on the action potential and transmembrane ion currents in rabbit ventricular myocytes to explore its antiarrhythmic property. The whole-cell patch clamp was used to record the action potential and ion currents, while the multichannel acquisition and analysis system was used to synchronously record the electrocardiogram and monophasic action potential. The results showed that 30 μmol/L Cur shortened the 50 and 90% repolarization of action potential by 17 and 7%, respectively. In addition, Cur concentration dependently inhibited the Late-sodium current (INa.L), Transient-sodium current (INa.T), L-type calcium current (ICa.L), and Rapidly delayed rectifying potassium current (IKr), with IC50 values of 7.53, 398.88, 16.66, and 9.96 μmol/L, respectively. Importantly, the inhibitory effect of Cur on INa.L was 52.97-fold higher than that of INa.T. Moreover, Cur decreased ATX II-prolonged APD, suppressed the ATX II-induced early afterdepolarization (EAD) and Ca2+-induced delayed afterdepolarization (DAD) in ventricular myocytes, and reduced the occurrence and average duration of ventricular tachycardias and ventricular fibrillations induced by ischemia–reperfusion injury. In conclusion, Cur inhibited INa.L, INa.T, ICa.L, and IKr; shortened APD; significantly suppressed EAD and DAD-like arrhythmogenic activities at the cellular level; and exhibited antiarrhythmic effect at the organ level. It is first revealed that Cur is a multi-ion channel blocker that preferentially blocks INa.L and may have potential antiarrhythmic property.

Highlights

Cardiovascular diseases (CVDs) are the leading global cause of mortality, and approximately half of this mortality contributes to sudden cardiac deaths (SCDs) (Go et al, 2014), which generally occur after malignant arrhythmia
The results showed that there was no significant effect of Cur on resting membrane potential (RMP), action potential amplitude (APA), or maximum depolarization velocity (Vmax) (Table 1)
By studying the effects of Cur on the I–V relationships, steady-stateactivation, and time-dependent recovery of ICa.L in ventricular myocytes, the results showed that Cur inhibited ICa.L in a concentration-dependent manner (Figure 2A) and the maximum current density of ICa.L was obtained at the test potential of 5 mV (Figure 2B)

Summary

Introduction

Cardiovascular diseases (CVDs) are the leading global cause of mortality, and approximately half of this mortality contributes to sudden cardiac deaths (SCDs) (Go et al, 2014), which generally occur after malignant arrhythmia. Most traditional antiarrhythmic drugs (AADs) are selective ion channel blockers, a large part of which are limited in clinical application due to their potential proarrhythmic effects and numerous side effects (Zdanowicz and Lynch, 2011). It is generally believed that an ideal AAD should have multiion channel effects, and one of which is the best target (Budillon et al, 2005; Nattel and Carlsson, 2006; Barman, 2015; Polak et al, 2015). Modern cardiology is still waiting for the introduction of safe and effective AADs. Over the years, cumulative randomized controlled trials of traditional natural products have demonstrated its efficacy and safety in patients with CVDs and gradually popularized worldwide (Brenyo and Aktas, 2014; Wang et al, 2014; Hua et al, 2019)

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