Vasodilatory effects of trans-3-methoxy-β-nitrostyrene, a synthetic nitroderivative, on rat thoracic aorta: involvement of soluble guanylate cyclase stimulation

Previously, we showed that vasorelaxant effects of trans -4-methoxy-β-nitrostyrene (T4MN) in rat aorta were mediated through stimulation of the soluble guanylate cyclase (sGC) pathway. The present study tested the hypothesis that bonding of the methoxy electron-donor group at the meta-position instead of the para-position into the aromatic moiety might enhance the interaction of the nitroderivative with sGC. For this purpose, vascular effects of the trans -3-methoxy-β-nitrostyrene (T3MN) were studied in rat aorta. In endothelium-intact preparations, T3MN was 100 times more potent as a vasorelaxant than its stereoisomer, T4MN. T3MN-induced vasodilatory effects remained unaffected by indomethacin, MDL-12,330A or glybenclamide but were significantly reduced by endothelium removal, L-NAME, ODQ, LY294002, TEA, 4-AP, and apamin. Under Ca 2+ -free conditions, T3MN was unresponsive to transient contractions evoked by caffeine, whereas it inhibited contractions induced by (i) the protein kinase C activator phorbol 12-myristate 13-acetate, (ii) the tyrosine phosphatase inhibitor sodium orthovanadate, (iii) exogenous calcium influx via receptor- or voltage-operated Ca 2+ channels and (iv), in an ODQ-preventable manner, those evoked by PHE or Ca 2+ influx through stores-operated Ca 2+ channels activated by thapsigargin-induced Ca 2+ store depletion. In conclusion, T3MN induced a potent vasorelaxant effect that seems to be mediated partly by an endothelium-dependent mechanism involving activation of the Akt/eNOS/NO pathway and partly by an endothelium-independent mechanism through activation of the sGC/cGMP/PKG pathway in vascular smooth muscle, leading to inhibition of Ca 2+ influx from the extracellular milieu and IP 3 -sensitive intracellular Ca 2+ release as well as activation of potassium channels.