The cardiac electrophysiology effects of higenamine in guinea pig heart

Background: Higenamine (HG) is an active compound derived from Aconiti root with a cardiotonic effect. It has been approved by the Chinese SFDA for clinical trials due to its effect as a potent inotropic and chronotropic agent in the heart. However, the direct mode of action of HG on cardiac electrophysiology is unclear.

Methods: The experiments were performed at both cell levels and the isolated organ. The major cardiac ion currents and the action potential duration (APD) were measured using patch-clamps in single guinea-pig left ventricular myocytes. ECG was recorded in isolated guinea pig hearts.

Results: In the left ventricular myocytes, HG increased I_Ca-L and I_Ks in concentration- and voltage-dependent manners in the left ventricular myocytes. It potentiated the I_Ca-L and I_Ks simultaneously for synchronization. The EC₅₀ values were 0.27 μM and 0.64 μM for the I_Ca-L and I_Ks, respectively. HG (0.1 μM, 0.5 μM and 1 μM) had no effect on the I_Kr and I_Na. HG slightly prolonged APD at lower concentrations, and shortened the APD at higher concentrations. HG can induce the delayed after depolarization (DAD), which showed some pro-arrhythmic effect. In the isolated perfused heart, HG increased the heart rate via an action on the sinoatrial node cells, but did not induce cardiac arrhythmias, even at high concentrations. The EC₅₀ value for the sinoatrial node that controls the heart rate was 0.13 μM. The sinoatrial node cells appeared to be more sensitive than ventricular myocytes to HG. The effects of HG on ventricular cells and sinoatrial node cells were both mediated through stimulation of β1-AR.

Conclusion: We show for the first time that HG produced a predominant action on the sinoatrial node. HG appears to control the cardiac electrophysiology through its predominant effect on the sinoarial node cells, without induction of the ectopic activity that causes cardiac arrhythmias. Thus, HG might be useful for the treatment of bradycardia.