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

• Treprostinil, iloprost and MRE-269 were investigated in rat pulmonary vasculature as prostacyclin (IP) receptor agonists.
• Treprostinil-induced relaxation of small pulmonary arteries pre-contracted with U46619, was fully antagonised by IP receptor antagonists.
• Iloprost-induced relaxation of pre-contracted small pulmonary arteries was partially inhibited by IP antagonists.
• Treprostinil- and iloprost-induced relaxations of small pulmonary veins were partially inhibited by IP antagonists.
• By contrast, MRE-265 induced relaxation of pulmonary arteries and veins were not inhibited by the selective IP antagonist.

The prostacyclin (IP) receptor agonists, treprostinil, iloprost and the selexipag metabolite, MRE-269 (ACT-333679) were evaluated in rat distal pulmonary blood vessels. Small pulmonary arteries and veins were pre-contracted with the thromboxane mimetic, U46619 (25 and 100 nM, respectively), and relaxation determined with and without IP receptor antagonists, RO1138452 and RO3244794. In arteries, treprostinil was a more potent vasorelaxant than iloprost, while the efficacy of iloprost was greater. In pulmonary arteries, treprostinil-induced relaxation was essentially abolished by both IP antagonists (1 μM), while responses to iloprost were partially inhibited. Both treprostinil and iloprost were equipotent, prominently relaxing pulmonary veins with responses being similarly and partially sensitive to IP antagonists. In contrast, RO1138452 failed to inhibit relaxations to MRE-269 in either pulmonary arteries or veins, suggesting no involvement of typical IP receptors. Thus, rat pulmonary tissues cannot be considered appropriate to assess classical IP receptors using the proposed highly selective non-prostanoid agonist MRE-269, contrasting with the IP receptor agonism profile of prostacyclin analogues, iloprost and treprostinil.