N-Methylberbamine extends the action potential of the cardiac ventricular myocytes of rabbits through inhibiting an outward rectifying current

Abstract

Background Accumulated data show that N-methylberbamine (N-MB), a berberine derivative, has marked antiarrhythmic effect through influencing the electric activities of cardiac ventricular myocytes. However, the underlying mechanisms are still ill-defined. In this study, the effects of N-MB on the action potential, L-type calcium current and outward rectifying current in the cardiac ventricular myocytes of rabbits were investigated to deduce its mechanism of anti-arrythmias. Methods The action potential and transmembrane ionic currents were elicited from the single rabbit ventricular myocytes under the whole-cell current/voltage clamp condition. And the binding of N-MB to Cav1.2 calcium channel or Kv11.1 potassium channel was evaluated by molecular docking technique. Results Following a 5 min perfusion with 1 micromolar N-MB containing Tyrode solution, the duration of action potentials (APD20, APD50 and APD90) were dramatically extended and the amplitude of action potential (APA) was partially reduced. N-MB decreased the amplitude of each peak ICa. Meanwhile, neither V1/2 nor K was altered significantly. In addition, N-MB not only abolished the feature of Itail completely, but also reduced its amplitude to zero level from control values at different membrane potentials from -20 mV to +50 mV. The results of molecular docking showed that N-MB could bind to the IV domain of Cav1.2 channel or Kv11.1 channel with higher binding scores than there corresponding inhibitors (verapamil or dofetilide), indicating that N-MB could bind to these two channels in a stable conformation. Conclusion N-MB inhibited the slow inward and outward rectifying currents, but meantime dramatically extended the action potential durations, indicating that the N-MB may perform its antiarrythmic efect through blocking both calcium and potassium channels.

This work was supported by grants form the NSFC (81100108) and the Key Laboratory of Medical Electrophysiology, Ministry of Education of China (201601, 201605).