Efeitos vasculares do 1-nitro-2-fenileteno, trans-4-metoxi-β-nitroestireno e trans-4-cloro-β-nitroestireno: relação estrutura-atividade

Abstract

1-Nitro-2-phenylethene, trans-4-methoxy-β-nitrostyrene and trans-4-chloro-β-nitrostyrene are synthesized from 1-nitro-2-phenylethane to improve its pharmacologically potency. In this study, we investigated the vasorelaxing effects of these nitroderivatives in different vascular bed preparations and studied structure-activity relationship. 1-Nitro-2-phenylethene (0,67-670,46 µM) presented vasorelaxing effects with similar power in phenylephrine or potassium-induced contractions in aortic rings, pulmonary artery and in phorbol-12,13-dibutyrate or sodium orthovanadate-induced contractions. Its action appears to occur intracellularly probably through inhibition of contractile events that are clearly independent of Ca2+ influx from the extracellular milieu, with independent-endothelial presence. In endothelium-intact mesenteric resistance arterial rings, 1-nitro-2-phenylethene also relaxed sustained contractions induced by noradrenaline, with an IC50 value (7.50 [3.28-11.66] µM) significantly lower than that obtained in aortic preparations (70.19 [31.37-109.01] µM). Because of the conformational restriction of its alkene moiety, 1-nitro-2-phenylethene was shown to be a vasorelaxant nearly 3.3 and 5.7 times more potent than its structural analogue 1-nitro-2-phenylethane respectively in conductance and resistance arteries. Trans-4-methoxy-β-nitrostyrene (0.55-558.12 µM) induced an endothelium-independent vasorelaxant effect with a higher potency on pharmacomechanical coupling than on electromechanically mediated induced contractions. The IC50 value for the relaxant effect of trans-4-methoxy-β-nitrostyrene in aortic preparations pre-contracted with phenylephrine was significantly higher following pretreatment with methyl blue [IC50 = 325.42 [197.81-453.09] or ODQ 188.88 [58.31-319.39 µM], when compared to control (IC50 = 78,23 [48,43-108,02] µM). These data provide substantial evidence that vasorelaxation induced by trans-4-methoxy-β-nitrostyrene is mediated through stimulation of soluble guanylate ciclase. As with 1-nitro-2-phenylethene, trans-4-methoxy-β-nitrostyrene possess greater potency in resistance (IC50 = 9.76 [0.78-18.80] µM) than conductance (IC50 = 78.23 [48.43-108.02] µM) arteries. Although the methoxy substitution in the para-position of the aromatic ring did not increase the 1-nitro-2-phenylethene´s vasorelaxant potency, it seems that stabilizing the nitroxyl free radical though a resonance effect explains the different mechanisms by which 1-nitro-2-phenylethene and trans-4-methoxy-β-nitrostyrene induce their vasorelaxant effects. The trans-4-chloro-β-nitrostyrene (0.54-544.69 µM) also induced an endothelium-independent vasorelaxant effect, but with a similar potency on both pharmacomechanical and electromechanical couplings. This effect seems also mediated by a soluble guanylate cyclase pathway as it was blunted following pretreatment with ODQ (IC50 = 157.63 [123.42-191.89] µM) or methylene blue (IC50 = 149.30 [31.12-267.49 µM).In conclusion, our findings indicate that the conformational restriction of its alkene moiety in 1-nitro-2-phenylethane has been responsible for increased its pharmacologically potency. Its vasorelaxation is of myogenic nature probably through inhibition of contractions that are independent of Ca2+ influx from the extracellular milieu differently than its structural analogue 1-nitro-2-phenylethane. The insertion of methoxyl grouping in 1-nitro-2-phenylethene’s aromatic ring did not contribute to be more powerful. But because of its electron donor character, stabilized the molecule, trans-4-methoxy-β-nitrostyrene most likely has its effects mediated through stimulation of soluble guanylate ciclase. Probably chlorine atom in trans-4-chloro-β-nitrostyrene promoted the molecular affinity with the enzyme guanylate cyclase. Our findings showed that these nitroderivatives are interesting and promising substances. Investigations should be continued in the cardiovascular system in normotensive animals and in hypertension models such pulmonary hypertension for example. Studies in erectile dysfunction, heart attack, and others diseases are relevant too. More complex searches in vitro in resistance arteries or coronary arteries are also important. Also in silico studies involving the of guanylate cyclase and cGMP measurement, especially with trans-4-chloro-β-nitrostyrene and trans-4-methoxy-β-nitrostyrene should be done.