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Planta Med 2019; 85(09/10): 738-744
DOI: 10.1055/a-0942-4502
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Higenamine, a Dual Agonist for β 1- and β 2-Adrenergic Receptors Identified by Screening a Traditional Chinese Medicine Library

Yanmin Chen
1   Institute of Molecular Medicine, Peking University, Beijing, China
,
Bujing Guo
1   Institute of Molecular Medicine, Peking University, Beijing, China
,
Hongda Zhang
1   Institute of Molecular Medicine, Peking University, Beijing, China
,
Lihong Hu
2   Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
,
Jue Wang
1   Institute of Molecular Medicine, Peking University, Beijing, China
› Author Affiliations
Further Information

Publication History

received 24 October 2018
revised 18 May 2019

accepted 23 May 2019

Publication Date:
11 June 2019 (online)

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Abstract

Chronic heart failure is the terminal stage of various cardiovascular diseases. Despite the availability of several classes of drugs, there is still an unmet need for effective treatment. Based on bench work during the past two decades, we have proposed that enhancement of β 2-adrenergic receptor signaling in combination with the presently preferred β 1-adrenergic receptor blockade would be a promising strategy. Chinese herbal medicines have been shown to be effective in the treatment of heart failure, although the mechanisms largely remain unknown. In the present study, we screened an herbal medicine compound/extract library for β-adrenergic receptor ligands to determine the target of certain effective botanical remedies and seek a leading compound(s) for chronic heart failure treatment. Using a high-throughput screening assay, we identified higenamine, which has a long history in chronic heart failure treatment in traditional Chinese medicine, to be a potent β-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both β 1-adrenergic receptor and β 2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a β 2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine. In conclusion, we found an herbal compound, higenamine, to be a dual agonist for β 1/β 2-adrenergic receptors with no preference in stimulating the Gs and Gi pathways in β 2-adrenergic receptor signaling. Our results elucidated not only the target of higenamine to explain its pharmacological effect in treating chronic heart failure, but also the mechanisms of its cardiac toxicity.

Key words

chronic heart failure - β-adrenergic receptor - biased signaling - agonist - higenamine

Supporting Information

    The establishment and verification of the screen assay using isoproterenol are provided as Supporting Information.

  • Supporting Information
 

  • References

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