In vitro pharmacological characterization of the prostanoid receptor population in the non-pregnant porcine myometrium

Abstract

In order to characterize prostanoid receptors present in the non-pregnant porcine uterus, the effects of naturally occurring prostaglandins (D 2, E 2, F 2α, I 2) and synthetic prostanoid receptor agonists on contractility of the longitudinal and circular muscles were examined in vitro. The potent contractile actions of prostaglandin F 2α and cloprostenol indicate the presence of excitatory FP receptors in the porcine uterus. The longitudinal muscle was more sensitive to FP receptor agonists than was the circular muscle. Prostaglandin D 2 produced an excitatory response in the longitudinal muscle but completely inhibited the spontaneous contraction of the circular muscle. BW-245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin, 1 nM–10 μM, a DP receptor agonist) inhibited the spontaneous contractions of both muscles, but the inhibition was conspicuously stronger in the circular muscle. Prostaglandin I 2 caused excitatory and inhibitory responses in the longitudinal and circular muscles, respectively, at relatively high concentrations (10–100 μM). Cicaprost, an IP receptor agonist caused inhibition of the contraction in the circular muscle but contracted the longitudinal muscle. Iloprost, an EP 1/IP receptor agonist, caused excitatory responses in both muscles at relative high concentrations. Prostaglandin E 2 caused excitatory responses at 1–100 nM and inhibitory responses at 100 nM–10 μM in both muscle layers. ONO-DI-004 ((17 S)-2,5-ethano-6-oxo-17,20-dimethyl prostaglandin E 1, an EP 1 receptor agonist) and ONO-AE-248 ((16 S)-9-deoxy-9β-chloro-15-deoxy-16-hyfroxy-17,17-trimethylene-19,20-didehydro prostaglandin F 2, an EP 3 receptor agonist) contracted the longitudinal muscle but had little effect on the circular muscle. ONO-AE1-259 (11,15- O-dimethyl prostaglandin E 2, an EP 2 receptor agonist) inhibited the spontaneous contractions of both muscle layers to almost the same degree, but ONO-AE1-329 (16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia prostaglandin E 1, an EP 4 receptor agonist) did not inhibit the myometrial contraction. The present results indicate that contractile (FP, EP 1, EP 3) and relaxatory (DP, IP, EP 2) prostanoid receptors are present in the non-pregnant porcine uterus. There are marked muscle layer-related differences in the degree of responsiveness of prostanoid receptor agonists, and these differences suggest that there is a heterogeneous distribution of prostanoid receptors in the longitudinal and circular muscles (FP, EP 1 and EP 3, longitudinal muscle>circular muscle; DP, circular muscle>longitudinal muscle).