The Nitric Oxide/Soluble Cyclic Guanylase/Cyclic Guanosine Monophosphate Pathway Is Involved in the Cardiovascular Effects of a Novel α₁- and β-Adrenoceptor Antagonist

Abstract

The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α1- and β-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α1- and β-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α1- and β-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α1-adrenoceptors. Our results demonstrated that MH-78 possesses α1- and β-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway.