Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Abstract

{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI 2 ) 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 PGI 2 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 E 3 (EP 3 ) receptor mRNA was increased in pulmonary artery from MCT-PAH rats.In contraction experiments, the selective EP 3 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 EP 3 receptor antagonist (2E)-3-(3Ј,4Ј-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP 3 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.

Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Selexipag, an Orally Available Selective Prostacyclin Receptor Agonist, in Healthy Subjects

“…Treprostinil induced weaker relaxation of the pulmonary artery in control rats, whereas no relaxation was observed in the pulmonary artery from monocrotaline-treated rats. Furthermore, ACT-333679, but not treprostinil, induced a concentration-dependent relaxation of both intra- and extra-lobular pulmonary arteries pre-contracted with endothelin-1, a known mediator of PAH [28,29,30]. At present, it is not known if these preclinical findings will translate in a superior efficacy and/or safety profile of selexipag when compared to treprostinil.…”

Differential actions of the prostacyclin analogues treprostinil and iloprost and the selexipag metabolite, MRE-269 (ACT-333679) in rat small pulmonary arteries and veins

“…Furthermore, the importance of signalling through a family of transcription factors called peroxisome proliferator-activated receptors (PPARs) is now widely recognised for both prostacyclin and its stable analogues [8,9]. For selexipag and its active metabolite, MRE-269 (ACT-333679), the IP receptor is considered to be the only significant target [10][11][12].…”

EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

“…Likewise, diminished relaxation of PAs in response to iloprost, treprostinil, and beraprost was reported in MCT-induced PAH in rats via a mechanism that involves stimulation of the contractile EP3 receptor (27,28). Furthermore, the EP3 receptor appears to be functionally upregulated in the PAs of MCT-treated rats (28), indicating that EP3 receptor may be involved in the pathogenesis of PAH.…”