Yuhong Wang1, Jing Geng2, Min Jiang2, Cong Li1, Yanxing Han1, Jiandong Jiang3. 1. State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China. 2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, 100050, China. 3. State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: jiand.jiang@163.com.
Abstract
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.
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.