Abstract 13829: The Active Metabolite of Selexipag Relaxes Rat Pulmonary Artery via Selective Activation of IP Prostacyclin Receptors
Introduction: Selexipag is a selective IP prostacyclin receptor agonist in development for the treatment of pulmonary arterial hypertension. Preclinical studies demonstrate that selexipag and its active metabolite ACT-333679 relax rat extralobar pulmonary artery (EPA) ex vivo. It has been reported that the IP receptor antagonist CAY10441 does not inhibit relaxation to ACT-333679.
Hypothesis: We hypothesized that relaxation of rat EPA to ACT-333679 could be inhibited by antagonism of IP receptors using a modified protocol.
Methods: Rings of rat EPA were prepared using standard techniques. Relaxation to ACT-333679 was measured in EPA pre-contracted with PGF2α(10 μM). The effect of CAY10441, BWA868C and PF04418948 (selective antagonists of relaxant IP, DP1andEP2receptors, respectively) on relaxation to ACT-333679 was measured using 2 protocols: (1) EPA was incubated with each receptor antagonist prior to addition of increasing concentrations of ACT-333679; (2) each receptor antagonist was added after stabilization of relaxation to ACT-333679 (1 μM).
Results: ACT-333679 relaxed EPA in a concentration-dependent manner (Figure 1A; control pEC50 5.8 ± 0.1). CAY10441 (1 μM) did not inhibit relaxation to ACT-333679 when added prior to ACT-333679 (pEC50 5.6 ± 0.1; not statistically significant vs control). However, CAY10441 (0.1-10 μM) reversed relaxation of EPA when added after sub-maximal relaxation to ACT-333679 (1 μM) was reached (relaxation 48.8 ± 9.8% of PGF2α contraction) (Figure 1B). BWA868C and PF04418948 did not inhibit relaxation of EPA when added before or after ACT-333679.
Conclusion: Relaxation of EPA to ACT-333679 is inhibited by antagonism of IP receptors, but not DP1or EP2 receptors. IP receptor activation by ACT-333679 is first required to observe the inhibitory effect of CAY10441 on vasorelaxation. ACT-333679 relaxes rat EPA via selective activation of IP prostacyclin receptors.
Author Disclosures: K. Morrison: Ownership Interest; Modest; Owns stock. Employment; Significant; Employee of Actelion Pharmaceuticals. R. Ernst: Employment; Significant; Employee of Actelion Pharmaceuticals. F. Haag: Employment; Significant; Employee of Actelion Pharmaceuticals. D. Bur: Employment; Significant; Employee of Actelion Pharmaceuticals. M. Clozel: Employment; Significant; Employee of Actelion Pharmaceuticals.
- © 2015 by American Heart Association, Inc.