A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary artery

2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) is an orally available, long-acting nonprostanoid prostacyclin receptor (IP receptor) agonist prodrug. In a rat model of pulmonary hypertension induced by monocrotaline (MCT), NS-304 ameliorated vascular endothelial dysfunction, pulmonary arterial wall hypertrophy, and right ventricular hypertrophy, and it elevated right ventricular systolic pressure and improved survival. {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), the active form of NS-304, is much more selective for the IP receptor than are the prostacyclin analogs beraprost and iloprost, which also have high affinity for the EP(3) receptor. To investigate the effect of receptor selectivity on vasodilation of the pulmonary artery, we assessed the relaxant response to these IP agonists in rats. MRE-269 induced vasodilation equally in large pulmonary arteries (LPA) and small pulmonary arteries (SPA), whereas beraprost and iloprost induced less vasodilation in SPA than in LPA. An EP(3) agonist, sulprostone, induced SPA and LPA vasoconstriction, and an EP(3) antagonist attenuated the vasoconstriction. Beraprost showed EP(3) agonism and induced LPA and SPA vasoconstriction, whereas the EP(3) antagonist inhibited this vasoconstriction and enhanced beraprost- and iloprost-induced SPA vasodilation. These findings suggest that the EP(3) agonism of beraprost and iloprost interfered with the SPA vasodilation resulting from their IP receptor agonism. Endothelium removal markedly attenuated the vasodilation induced by beraprost, but not that induced by MRE-269 or iloprost. Moreover, the vasodilation induced by beraprost and iloprost, but not that induced by MRE-269, was more strongly attenuated in LPA from MCT-treated rats than from normal rats. NS-304 is a promising alternative medication for pulmonary arterial hypertension with prospects for good patient compliance.