Efeito vasodilatador de três nitrocompostos aromáticos e estruturalmente relacionados em aorta isolada de rato: influência do grupo funcional NO2 no mecanismo de ação

Abstract

Compounds containing a nitro group may reveal vasodilator properties, recently, studies indicated that the aromatic nitro compounds 1-nitro-2-phenylethane and 2-nitro-1-phenyl-1-propanol exhibit vasodilatory effects in rats, such effects involved the participation of the guanylate cyclase-cGMP pathway and opening of K+ channels. In the present study, we evaluated the effects of 2-nitro-1-phenylethanone (NPeth), 1-nitro-2-propylbenzene (Npben) and 2-nitro-2-phenylpropane-1,3-diol (NPproprop) in vascular tissues isolated from rats. Isometric recordings were obtained from isolated rings of thoracic aorta or 2nd generation branchs mesenteric artery of Wistar rats. Tissues were suspended in isolated organs bath under physiological conditions. Docking and molecular dynamics simulations, in silico experiments, were realized for simulating complex formation between the nitro compounds with the enzyme guanylate cyclase (GC). In the aorta preparations contracted with K+ or phenylephrine (PHE), Npben and NPproprop induced total relaxation, and partially to addition of NPpropeth, being less effective. NPproprop showed higher potency and its effect was inhibited by pretreatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), methylene blue and MDL-12,330A. Endothelial removal or pre-treatment with indomethacin, L-NAME did not alter the relaxing effect of NPproprop on aortic rings. At lower concentrations, Npben increased PHE-induced contractions, although only in preparations with intact endothelium. This effect was inhibited by pre-treatment with L-NAME, indomethacin, ruthenium red and HC-030031, suggesting that the potentiating effect of Npben is dependent on endothelial integrity and probably involves the TRP (A1 and V4) endothelial channels. A set of experiments was conducted to removal of Ca2+ from the extracellular milieu, in these conditions, the NPproprop inhibited the contraction elicited preferentially by VOC channels, however, NPproprop was also able to abolish responses in the ROC channels, interestingly, this inhibitory effect was reversed completely after treatment with ODQ, the same fact occurred in the response mediated by activation of the IP3 receptor. In an ODQ-dependent manner, NPproprop inhibited the contraction induced by the protein kinase C activator phorbol 12,13-dibutyrate or by the tyrosine phosphatase inhibitor sodium orthovanadate. In the computational simulation the NPproprop was the nitro compound that presented greater binding energy with the guanylate cyclase. Finally, it was evidenced that NPproprop presented greater myorelaxant potency between 2nd generation branchs mesenteric artery to aorta. NPproprop stood out among the others nitro compounds for the probable stimulation of GC and activation of the guanylate cyclase-cGMP-PKG pathway. Aliphatic chain substituents selectively interfered to the ability of these compounds to induce vasorelaxant effects.