Identification of higenamine as a novel α₁ -adrenergic receptor antagonist

The α₁ -adrenoceptor (α₁ -AR) antagonists are potential candidates for the treatment of blood pressure. Higenamine (HG) is a novel α₁ -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 α₁ -AR in a concentration-dependent manner. The affinities (pKi) 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 α₁ -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 pA₂ 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 α₁ -AR and it appears to be a novel antagonist for α₁ -AR, which may contribute to its hypotensive effect.