title: The vasorelaxant effects of 1-nitro-2-phenylethane involve stimulation of the soluble guanylate cyclase-cGMP pathway.
abstract: 1-Nitro-2-phenylethane is the first organic NO₂-containing molecule isolated from plants. It possesses interesting hypotensive, bradycardic, and vasodilator properties, but the mode by which it induces vasorelaxation is still unknown. The underlying mechanism involved in the vasodilator effect of 1-nitro-2-phenylethane was investigated in rat aorta. The vasorelaxant effects of 1-nitro-2-phenylethane did not depend on endothelial layer integrity, and the effects were refractory to L-N(G)-nitroarginine methyl ester (L-NAME)-induced nitric oxide synthase inhibition. Vasorelaxation was similarly resistant to treatment with indomethacin, cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride (MDL-12330A), and KT5720, indicating that neither prostaglandin release nor adenylyl cyclase activation is involved. Conversely, methylene blue- and ODQ-induced guanylate cyclase inhibition reduced the vasorelaxation induced by 1-nitro-2-phenylethane. The pharmacological blockade of K(+) channels with tetraethylammonium, glybenclamide, and 4-aminopyridine also blunted vasorelaxation induced by 1-nitro-2-phenylethane. The effects of 1-nitro-2-phenylethane were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and comparable to the effects induced by sodium nitroprusside. In silico analysis using an Ns H-NOX subunit of guanylate cyclase revealed a pocket on the macromolecule surface where 1-nitro-2-phenylethane preferentially docked. In vitro, 1-nitro-2-phenylethane increased cyclic guanosine 3',5'-monophosphate (cGMP) levels in rat aortic rings, an effect also reversed by ODQ. In conclusion, 1-nitro-2-phenylethane produces vasodilator effects by stimulating the soluble guanylate cyclase-cGMP pathway.
authors.affiliation: Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Brazil.
authors.forename: Teresinha S
authors.initials: TS
authors.lastname: Brito
authors.forename: Francisco J B
authors.initials: FJ
authors.lastname: Lima
authors.forename: Karoline S
authors.initials: KS
authors.lastname: Aragão
authors.forename: Rodrigo J B
authors.initials: RJ
authors.lastname: de Siqueira
authors.forename: Pergentino J C
authors.initials: PJ
authors.lastname: Sousa
authors.forename: José G S
authors.initials: JG
authors.lastname: Maia
authors.forename: Jairo D
authors.initials: JD
authors.lastname: Filho
authors.forename: Saad
authors.initials: S
authors.lastname: Lahlou
authors.forename: Pedro J C
authors.initials: PJ
authors.lastname: Magalhães
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C541822:1-nitro-2-phenylethane; D001555:Benzene Derivatives; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP