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.