TY - JOUR T1 - Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 547 LP - 555 DO - 10.1124/jpet.112.197152 VL - 343 IS - 3 AU - Keith Morrison AU - Rolf Studer AU - Roland Ernst AU - Franck Haag AU - Katalin Kauser AU - Martine Clozel Y1 - 2012/12/01 UR - http://jpet.aspetjournals.org/content/343/3/547.abstract N2 - {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI2) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI2 analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E3 (EP3) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP3 receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP3 receptor antagonist (2E)-3-(3′,4′-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP3 receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease. ER -