LAUSR

Abstract 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‐&bgr;‐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. Graphical abstract Figure. No Caption available.