Identification of higenamine as a novel α₁‐adrenergic receptor antagonist

Abstract

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.

Therapeutic effects of higenamine combined with [6]‐gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function

“…β2‐AR activation explains the pharmacological effect of HG/aconite in treating CHF by enhancing the contractile response and reducing cardiomyocyte apoptosis . Also, HG is identified as a novel α1‐AR antagonist, which may contribute to its hypotensive effect and suppression platelet aggregation . Pharmaceutically, it has multiple pharmacological effects, including positive inotropic effect, dilations of blood vessels and bronchi, anti‐inflammatory activity, antispasmodics, anti‐thrombotic, anti‐oxidative and anti‐apoptotic properties .…”

Relaxant Activities of Extracts from Uvaria rufa Blume and Caesalpinia sappan L. on Excised Rat’s Prostate Strips

“…Isoflavones, a flavonoid from red clover (Trifolium pratense), exhibited a relaxant effect on the smooth muscles of isolated guinea-pigs' ilea [44], rats' uteri [45], guinea-pigs' gall bladders [46] and rats' prostate glands [31]. Furthermore, a variety of flavonoids derived from various plant materials possessed α1-adrenergic receptor antagonists and reduced the contraction of the prostate smooth muscles of experimental animals [29][30][31][32].…”

“…β-sitosterol has been detected in ethyl acetate extracts from U. rufa stems [28]. Different types of flavonoids, alkaloids and sterols derived from various plant materials possessed α1-adrenergic receptor antagonists and exhibited relaxation effects on the dynamic component in the prostate gland of experimental animals [29][30][31][32]. Although there is a lot of research being done on the phytochemical composition of C. sappan and U. rufa, there is no detailed information about their relaxant properties on the prostate smooth muscles.…”

Not Just from Ethanol. Tetrahydroisoquinolinic (TIQ) Derivatives: from Neurotoxicity to Neuroprotection

“…On the other hand, Zhang et al (2019) suggested that higenamine, directly binding to α1-adrenergic receptors, could be an innovative α1-adrenergic receptor antagonist. In particular, in different models of hypertension (normotension and spontaneous hypertension), higenamine was able to decrease the blood pressure (Zhang et al 2019).…”