title: 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.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kubacka
authors.forename: Szczepan
authors.initials: S
authors.lastname: Mogilski
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Raźny
authors.forename: Jacek
authors.initials: J
authors.lastname: Sapa
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Waszkielewicz
authors.forename: Henryk
authors.initials: H
authors.lastname: Marona
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C000601923:1-(2,6-dimethylphenoxy)-3-(4-(2-(2-methoxyphenoxy)ethyl)piperazin-1-yl)propan-2-ol; D058668:Adrenergic alpha-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D010647:Phenyl Ethers; D010879:Piperazines; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D009569:Nitric Oxide; D011189:Potassium Chloride; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D008729:Methoxamine; D009638:Norepinephrine; D004837:Epinephrine