Identification of higenamine as a novel α1‐adrenergic receptor antagonist
2019
Zhang, Nana | Qu, Kai | Wang, Minjie | Yin, Qian | Wang, Wenjing | Xue, Lixiang | Fu, Haian | Zhu, Haîbo | Li, Zijian
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 α₁A‐, α₁B‐, and α₁D‐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 [³H]‐prazosin to α₁‐AR in a concentration‐dependent manner. The affinities (pKi) of HG for the cloned α₁A‐, α₁B‐, and α₁D‐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.
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