State Key Laboratory for Bioactive Substances and Functions of Natural Medicines; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
School of Basic Medical Sciences, Inner Mongolia Medical University, Jinshan Development District, Hohhot, PR China.
Phytother Res. 2019 Mar;33(3):708-717. doi: 10.1002/ptr.6261. Epub 2019 Jan 15.
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.
α-肾上腺素受体（α-AR）拮抗剂是治疗血压的潜在候选药物。盐酸育亨宾（HG）是一种新型的α-AR 拮抗剂。在这项研究中，我们在体外转染了α1-、α2-和α2-AR 的 HEK293A 细胞、大鼠肠系膜动脉、Wistar-Kyoto 大鼠和自发性高血压大鼠体内研究了 HG 的作用。放射性配体结合测定表明，HG 以浓度依赖性方式竞争性抑制[H]-哌唑嗪与α-AR 的结合。HG 对克隆的α1-、α2-和α2-AR 的亲和力（pKi）分别为 6.57、6.48 和 6.35，表明 HG 对三种α-AR 亚型没有选择性。在体外研究中，HG 能够阻断肌醇单磷酸的产生。它还显示出对苯肾上腺素（PE）诱导的钙离子内流和进入以及细胞外信号调节激酶 1 和 2 的磷酸化的抑制作用。在离体研究中，PE 引起了剂量依赖性的变力反应曲线，HG 的 pA 值为 6.86±0.29。此外，体内结果表明，HG 可降低正常血压、自发性高血压和 PE 诱导的高血压模型中的血压。这些结果表明，HG 可以直接与α-AR 结合，并且似乎是一种新型的α-AR 拮抗剂，这可能有助于其降压作用。
