Identification of higenamine as a novel α₁‐adrenergic receptor antagonist

The α 1 ‐adrenoceptor (α 1 ‐AR) antagonists are potential candidates for the treatment of blood pressure. Higenamine (HG) is a novel α 1 ‐AR antagonist. In this study, we investigated the effects of HG in HEK293A cells transfected with α 1A ‐, α 1B ‐, and α 1D ‐AR in vitro, rat mesenteric artery ex vivo, Wistar–Kyoto rats and spontaneously hypertensive rats in vivo. The radioligand binding assay showed that HG competitively inhibited the binding of [ 3 H]‐prazosin to α 1 ‐AR in a concentration‐dependent manner. The affinities ( p Ki) of HG for the cloned α 1A ‐, α 1B ‐, and α 1D ‐AR were 6.57, 6.48, and 6.35, respectively, indicating that HG displayed no selectivity for the three α 1 ‐AR subtypes. In in vitro studies, HG was able to blunt inositol monophosphate production. It also displayed an inhibitory effect on the influx and entry of calcium ions and phosphorylation of extracellular signal‐regulated kinase 1 and 2 induced by phenylephrine (PE). In ex vivo studies, PE caused a dose‐dependent inotropic response curve, and the pA 2 value for HG was 6.86 ± 0.29. In addition, the in vivo results showed that HG could decrease the blood pressure in normotension, spontaneous hypertension, and PE‐induced hypertension models. These results indicate that HG can directly bind to α 1 ‐AR and it appears to be a novel antagonist for α 1 ‐AR, which may contribute to its hypotensive effect.