Identification of higenamine as a novel α -adrenergic receptor antagonist.

The α -adrenoceptor (α -AR) antagonists are potential candidates for the treatment of blood pressure. Higenamine (HG) is a novel α -AR antagonist. In this study, we investigated the effects of HG in HEK293A cells transfected with α -, α -, and α -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 [ H]-prazosin to α -AR in a concentration-dependent manner. The affinities (pKi) of HG for the cloned α -, α -, and α -AR were 6.57, 6.48, and 6.35, respectively, indicating that HG displayed no selectivity for the three α -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 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 -AR and it appears to be a novel antagonist for α -AR, which may contribute to its hypotensive effect.