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1-Nitro-2-phenylethene (NPe) induces a more potent vasorelaxant effect in rat aorta than its structural analog 1-nitro-2-phenylethane, but mediated through a different mechanism, independent of soluble guanylate cyclase (sGC) stimulation. We hypothesized that introducing an electron donor into the aromatic moiety might stabilize NPe, enhancing its potency and/or interaction with sGC. Therefore, trans-4-methoxy-β-nitrostyrene (T4MN) was synthesized, and mechanisms underlying its vasorelaxant effects were studied in rat aortic ring preparations. In endothelium-intact preparations, T4MN fully relaxed contractions induced by phenylephrine (PHE) with a potency similar to that of its parent drug, NPe. This vasorelaxant effect that was unchanged by endothelium removal, pretreatment with L-NAME, indomethacin, or MDL-12,330 A, but was significantly reduced by tetraethylammonium, 4-aminopyridine, methyl blue, or ODQ. Under Ca2+-free conditions, T4MN did not alter contractions evoked by caffeine, but significantly reduced, in an ODQ-preventable manner, those induced by either PHE or extracellular Ca2+ restoration following depletion of intracellular Ca2+ stores in thapsigargin-treated aortic preparations. Under the same conditions, T4MN also reduced contractions induced by protein kinase C activator phorbol-12,13-dibutyrate with a potency similar to that evoked by this nitroderivative against PHE-induced contractions. In conclusion, T4MN induces potent vasorelaxation in rat aorta by stimulating the sGC-cGMP pathway through a NO-independent mechanism. Introduction of a methoxy group into the aromatic moiety apparently stabilizes NPe, thereby enhancing its interaction with sGC.