Evidence for the Presence of AH 13205-Sensitive EP2-Prostanoid Receptors in the Pregnant Baboon But Not in the Pregnant Sheep Myometrium Near Term

Abstract

Objective: Our purposes were to asses the effects of prostaglandin (PG) E₂ and PGF_2α on myometrial contractility in pregnant sheep and baboons in an in vitro superfusion study, and to characterize further the PGE-sensitive (EP) receptor subtype involved in the myometrial response to PGE₂ by using the selective prostanoid EP₂ agonist AH 13205.

Methods: Strip preparations of uterine muscle from 15 sheep (107-145 days' gestational age) and ten baboons (158-185 days' gestation) were studied. Cumulative concentration-response curves (CRC) were constructed to oxytocin (4.2 pmol/L to 0.42 μmol/L, PGE₂ (0.1 nmol/L to 1 μmol/L), and PGF_2α (1 nmol/L to 100 μmol/L), and 50% effective concentration (EC50) values (mean and 95% confidence interval) were calculated. We also tested the hypothesis that PGE₂-induced myometrial relaxation in pregnant baboons could be mediated by EP₂-prostanoid receptors. Myometrial strips were stimulated by oxytocin (0.42 nmol/L), and CRCs to the EP₂-agonist AH 13205 (0.1 nmol/L to 10 μmol/L) were constructed.

Results: Prostaglandin F_2α stimulated myometrial activity in a concentration-related fashion in all preparations from both sheep and baboons. The EC50 in the sheep myometrium for PGF_2α (52 nmol/L, 95% confidence interval [CI] 25-110) was significantly (P < .05) lower than that in baboon myometrium (183 nmol/L, 95% CI 93-355). Oxytocin stimulated myometrial activity in preparations of both sheep (EC50 = 0.29 nmol/L, 95% CI 0.11-0.71) and baboon (EC50 = 0.31 nmol/L, 95% CI 0.18-0.52). In contrast, responses to PGE₂ were species-related: PGE₂ caused concentration-related stimulation of myometrial activity in sheep tissue (EC50 = 3.2 nmol/L, 95% CI 2.0-5.0), but induced concentration-related inhibition of activity in baboon myometrium (50% inhibitory concentration [IC50] = 21 nmol/L, 95% CI 2.2-203). A concentration-related inhibitory response to AH 13205 (IC50 = 3.56 nmol/L, 95% CI 1.28-5.99) was obtained in the baboon. In contrast, AH 13205 failed to inhibit comparable myometrial strip preparations from pregnant sheep.

Conclusions: The present studies suggest that both sheep and baboon myometrium contain prostanoid receptors that mediate stimulation. In addition, baboon myometrium, like that from the human, contains AH 13205-sensitive EP receptors (EP₂ receptors), which mediate inhibition. The pregnant baboon may therefore represent a suitable animal model for investigations into the use of EP₂ agonists for the prevention of premature labor in humans.