The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum

Abstract

Higenamine mediates cardiotonic, vascular relaxation and bronchodilator effects. The relaxation effects and the mechanism of action of higenamine on the rat corpus cavernosum (CC) were assessed to investigate the effect of higenamine on penile erection. Strips of CC and aorta were used in organ baths for isometric tension studies. Tension was measured with isometric force transducers, and muscle relaxation was expressed as the percent decrease in precontraction induced by phenylephrine (PE). The relaxation reactions were investigated in an endothelial-denuded group and groups pretreated with N(G)-nitro-L-arginine methyl ester (NO synthesis inhibitor), propranolol (b-receptor blocker), indomethacin (COX inhibitor), glibenclamide (K þ ATP channel inhibitor), 4-aminopyridine (membrane potential-dependent potassium channel inhibitor) and methylene blue (guanylyl cyclase inhibitor) for 30 min. Intracavernous pressure (ICP) was assessed in rats after the intravenous administration of higenamine, and changes in guanosine 3 0 ,5 0 -cyclic monophosphate and adenosine 3 0 ,5 0 -cyclic monophosphate (cAMP) concentrations were measured on the basis of the higenamine concentration. Also, the combined reaction of higenamine and the phosphodiesterase type-5 (PDE-5) inhibitors was assessed. Higenamine induced relaxation of the CC and the aortic strips precontracted with PE in a dose-dependent manner. The CC was significantly more relaxed than the aortic rings in response to the same higenamine concentration (Po0.05). The CC relaxation reaction was suppressed by the b-receptor blocker propranolol. The cAMP concentration increased gradually with increased higenamine concentration (Po0.05). The ICP also increased with increased higenamine concentration in vivo (Po0.05). In the group pretreated with 10 À7 M higenamine, the relaxation reaction of CC induced by the PDE-5 inhibitor increased significantly, compared with CC exposed to the PDE-5 inhibitor but not pretreated with higenamine (Po0.05). In conclusion, higenamine induced relaxation of the rat CC in a dose-dependent manner. The effect may be mediated through b-adrenoceptors. The results suggest that higenamine may be valuable as a new lead compound for treating erectile dysfunction.

Pharmacological effects of higenamine based on signalling pathways and mechanism of action

“… Tsukiyama et al (2009 ) and Ueki et al (2011) isolated HG from the fruit of Nandina domestica Thunberg and found that HG stimulated β2-AR and had relaxing effects on the corpus cavernosum of Sprague-Dawley (SD) rats and bronchial smooth muscle. Kam et al (2012) demonstrated that HG caused the rat corpus cavernosum to relax in a dose-dependent manner and enhanced the relaxation response of the corpus cavernosum induced by a PDE-5 inhibitor (a drug for the treatment of penile erectile dysfunction). This vascular smooth muscle relaxation response is mediated by cGMP and cAMP.…”

“…In rats, the increased expression of cGMP and cAMP in cells causes dephosphorylation of the myosin light chain, resulting in relaxation of the corpus cavernosum smooth muscle. ( Ballard et al, 1998 ) Kam et al (2012) found that the expression of cGMP and cAMP increased under the action of HG, indicating that the mechanism of action of HG may be associated with the β-AR/cAMP and guanylate cyclase/cGMP signalling pathways.…”

Identification of higenamine as a novel α1‐adrenergic receptor antagonist

“…It exerts a protective effect on ischemia/reperfusion cardiac injury through activating the pathway of PI3K/AKT (Lee et al, ). HG is therapeutically useful in heart failure (Liu, Zhou, & Zeng, ), sepsis (Park et al, ), and erectile dysfunction (Kam et al, ). However, the relationship between HG and α 1 ‐AR has never been addressed.…”

Clinical safety assessment of oral higenamine supplementation in healthy, young men

“…3 This1-benzyl-1,2,3,4-tetrahydroisoquinoline alkaloid has been used to improve cardiac left ventricular function 4 and to stimulate -adrenergic receptors (-AR). 5 It has also been suggested to yield vasorelaxation properties 6 and to impart antiplatelet aggregation. 7,8 Due to the above-stated effects, some believe that intravenous higenamine may be a candidate agent for use in pharmacological stress testing (in conjunction with myocardial perfusion imaging).…”