Bupleurum Exerts Antiarrhythmic Effects By Inhibiting L-type Calcium Channels In Mouse Ventricular Myocytes

Background:Bupleurum（Bup）,a traditional Chinese herbal medicine,has been used to treat colds and fever for many years clinically.Studies have demonstrated that Bup has cardioprotective,anti-inflammatory,anticancer,antipyretic,antibacterial,antiviral and other biological activities,but the studies of Bup on cardiac electrophysiology have not been reported yet.Aims:In this study,the effects of Bup on arrhythmias and its mechanism were explored by studying the effects of Bup on aconitine-induced ventricular arrhythmias in mice as well as the effects of Bup on the action potential（AP）and various transmembrane ionic currents in mouse ventricular myocytes.Methods:The effects of Bup on aconitine-induced ventricular arrhythmias were investigated by electrocardiogram（ECG）recording in mice.The ventricular myocytes were obtained by acute isolation with enzymatic hydrolysis,and then the whole-cell patch-clamp technique was used to record the effect of Bup on AP and transient-sodium current(I_Na.T),the ATX II increased late sodium current(I_Na.L),L-type calcium current(I_Ca.L),transient outward current(I_to),delayed rectifier potassium current（I_K）or inward rectifier potassium current(I_K1)in ventricular myocytes to investigate the mechanism of Bup on arrhythmias.Results:Firstly,Bup decreased the incidence of ventricular fibrillation（VF）induced by aconitine and effectively delayed the onset time of ventricular tachycardia（VT）induced by aconitine in mice.Secondly,Bup（40 mg/m L）suppressed high-Ca²⁺-induced（3.6 mmol/L Ca Cl₂）delayed afterdepolarizations（DADs）and shortened the APD₅₀ and APD₉₀ to 60.89%±8.40%and 68.94%±3.24%of the control,respectively.Moreover,Bup（10,20,40,and 80 mg/m L）inhibited I_Ca.L in a concentration-dependent manner,with an IC₅₀ value of 25.36 mg/m L.At last,Bup affected the gated kinetics of L-type calcium channels by slowing down the steady-state activation,accelerating the steady-state inactivation,and delaying the inactivation-recovery processes.However,Bup had no significant effects on I_Na.T,ATX II-increased I_Na.L,I_to,I_K or I_K1in mouse ventricular myocytes.Conclusion:Bup may exert antiarrhythmic effects via inhibiting L-type calcium channels,of which wide clinical application also guarantees the safety of Bup.Therefore,Bup has the potential to be a safe and effective antiarrhythmic drug.