Vasorelaxant effects of 2‐nitro‐1‐phenyl‐1‐propanol in rat aorta

Abstract

2-Nitro-1-phenyl-1-propanol (NPP) is a nitro alcohol that is known as an intermediate in the synthesis of sympathomimetic agents, such as norephedrine. The present study investigated the vasoactive effects of NPP on rat aorta. In endothelium-intact aortic rings, NPP fully relaxed contractions that were induced by phenylephrine, KCl, and U-46619. The relaxant effects of NPP on phenylephrine-elicited contractions remained unaffected by NG-nitro-l-arginine methyl ester (l-NAME), indomethacin, propranolol, tetraethylammonium, 4-aminopyridine, and glibenclamide. Conversely, pretreatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride (MDL-12,330A), and N-[2-(P-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) reduced the ability of NPP to relax contractions that were elicited by phenylephrine. NPP inhibited the vasoconstrictor response that was induced by Ca in aortic rings that were stimulated by pharmacomechanical or electromechanical coupling with phenylephrine and 60 mmol/L KCl, respectively, and after the depletion of intracellular Ca stores. Such effects of NPP were significantly reversed by pretreatment with the guanylyl cyclase inhibitor ODQ and weakly influenced by the adenylyl cyclase inhibitor MDL-12,330A. In Ca -free medium, NPP inhibited transient contractions that were induced by phenylephrine but not caffeine. In homogenates of aortic rings, NPP increased cyclic guanosine 3',5'-monophosphate (cGMP) and cyclic adenosine 3'-5'-monophosphate levels, but this effect was statistically significant only for cGMP. In conclusion, in contrast to the vasoconstrictor amine norephedrine, NPP is a vasodilator in rat aorta, and its relaxant effects are likely attributable to cGMP production.

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

“…The conclusion of an endothelium-independent mechanism is also plausible from the experiments using KCl as a contractile agent, since the EC 50 of NPB to relax KCl-induced contractions in endothelium-intact or endothelium-denuded aorta did not differ when compared one another. These findings allow the conclusion that the relaxing effects of NPB did not involve endothelial mechanisms, a convergent aspect in relation to other NPB analogues [1, 3,[8][9][10].…”

“…Although deprived of endothelial influence to induce relaxation, NPB augmented (at concentrations between 30 and 300 lM) the magnitude of the phenylephrine-induced contraction. This phenomenon was a novelty, at least in relation to the nitro compounds previously tested [1, 3,[8][9][10] and it seems to be endotheliumdependent. In fact, the augmentation phase in the phenylephrine-induced contraction in response to NPB did not occur in endothelium-denuded preparations.…”

“…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).…”

“…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 . Chemically, the difference between 1‐nitro‐2‐phenylethane and β‐phenylethylamine, as well as between 2‐nitro‐1‐phenyl‐1‐propanol and phenylpropanolamine, is the presence of the NO 2 instead of an amine group, suggesting that such functional groups determine the pharmacological targets and, thus, a vasodilator profile for those possessing the NO 2 group.…”

“…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 .…”