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Published on: March 18, 2019
The cardiac electrophysiology effects of higenamine in guinea pig heart
Yuhong Wang1, Jing Geng2, Min Jiang2
1State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China.
Insights
Higenamine (HG) primarily affects the sinoatrial node, increasing heart rate without causing arrhythmias. This suggests HG is a potential treatment for bradycardia.
Area of Science:
- Cardiology
- Pharmacology
- Electrophysiology
Background:
- Higenamine (HG) is a cardiotonic compound from Aconiti root.
- HG is approved for clinical trials in China for its inotropic and chronotropic effects.
- The precise mechanism of HG on cardiac electrophysiology remains unclear.
Purpose of the Study:
- To elucidate the direct effects of Higenamine on cardiac electrophysiology.
- To investigate the impact of HG on ion currents and action potential duration.
- To determine the role of HG in sinoatrial node function and potential arrhythmogenic effects.
Main Methods:
- Experiments conducted at cellular and isolated organ levels.
- Patch-clamp technique used to measure cardiac ion currents (ICa-L, IKs, IKr, INa) and action potential duration (APD) in guinea-pig ventricular myocytes.
- Electrocardiogram (ECG) recorded in isolated guinea pig hearts.
Main Results:
- Higenamine increased ICa-L and IKs in a concentration- and voltage-dependent manner, with EC50 values of 0.27 μM and 0.64 μM, respectively.
- HG did not affect IKr or INa. It prolonged APD at low concentrations and shortened it at high concentrations, inducing delayed afterdepolarizations (DAD).
- In isolated hearts, HG increased heart rate (EC50 = 0.13 μM for sinoatrial node) via β1-adrenergic receptor (β1-AR) stimulation, without inducing arrhythmias.
Conclusions:
- Higenamine predominantly acts on the sinoatrial node, controlling cardiac electrophysiology.
- HG's effects on ventricular and sinoatrial node cells are mediated by β1-AR stimulation.
- HG shows potential for treating bradycardia due to its sinoatrial node effects and lack of arrhythmogenic activity.
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 ICa-L and IKs in concentration- and voltage-dependent manners in the left ventricular myocytes. It potentiated the ICa-L and IKs simultaneously for synchronization. The EC50 values were 0.27 μM and 0.64 μM for the ICa-L and IKs, respectively. HG (0.1 μM, 0.5 μM and 1 μM) had no effect on the IKr and INa. 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.
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