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.

Endothelium‐dependent and endothelium‐independent effects of 1‐nitro‐2‐propylbenzene on rat aorta

“…This pharmacological potency was lower than that evoked by other structurally related nitro compounds in the same preparations. The relaxant effects of its analogues on the contractions induced by phenylephrine yielded EC 50 varying between ~30 to 230 μ m . In common, these studies dealt with compounds possessing the NO 2 group in the α‐ or β‐carbon of the aliphatic chain ( Figure , panels c to f).…”

“…Substitutions in the aliphatic chain have been demonstrated to impact directly in their effects. 1‐Nitro‐2‐phenylethane ( Figure c), for instance, relaxes rat aorta preparations , but its analogue β‐phenylethylamine ( Figure a) causes aortic constriction in vitro, probably by acting on specific trace‐amine associated receptors . The nitro compound 2‐nitro‐1‐phenyl‐1‐propanol ( Figure d) relaxes rat aorta and mesenteric arteries , whereas its analogue phenylpropanolamine ( Figure b), a sympathomimetic active principle of over‐the‐counter nasal decongestants, reveals vasoconstrictor properties .…”

“…In the rat aorta, the vasodilator effects of 1‐nitro‐2‐phenylethane and 2‐nitro‐1‐phenyl‐1‐propanol involved stimulation of the soluble guanylyl cyclase (sGC) and the consequent production of cyclic guanosine monophosphate (cGMP) . In silico analysis predicted that the presence of the NO 2 allowed the putative interaction of the 1‐nitro‐2‐phenylethane with a binding site in the sGC regulatory subunit . Curiously, substitution at β‐carbon of 1‐nitro‐2‐phenylethane by a ketone, such as in the 2‐nitro‐1‐phenylethanone ( Figure e), abolished its vasorelaxant effect through the sGC pathway .…”

Mechanisms underlying the antihypertensive effect of Alstonia scholaris

“…For an endothelium-independent vasodilator, possible mechanisms that may be involve in its inhibition of any of the downstream steps in the contractile apparatus (Allen and Walsh, 1994;Brito et al, 2013;Park et al, 2009).…”

New insights into the role of soluble guanylate cyclase in blood pressure regulation

“…For example, resolving the crystal structure of the binding of the sGC activator BAY 60–2770 to an NO-sensitive heme domain homologous to sGC demonstrated that BAY 60–2770 shows a slightly more efficient conformational shift of the heme-binding domain than its parent compound cinaciguat, explaining its marginally more potent stimulation of sGC activity [48*]. And finally, the vasodilatory molecule 1-nitro-2-phenylethane was recently characterized as a novel heme-dependent sGC stimulator, distinct from the previously discovered riociguat-related compounds [49]. All these compounds hold great therapeutic potential in a variety of cardiovascular and other defects related to sGC dysfunction.…”