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 G_i inhibitor) indicated that it is a β ₂-adrenergic receptor G_s/G_i 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 G_s and G_i 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.

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