Agonist and antagonist specificities of decidual prostaglandin-releasing oxytocin receptors and myometrial uterotonic oxytocin receptors in pregnant rats
in ReproductionThis paper describes further pharmacological characterization of the decidual prostaglandin-releasing oxytocin receptors and the myometrial uterotonic oxytocin receptors in the uterus of the pregnant rat. The effects of oxytocin, arginine-vasopressin and their related agonists and antagonists on the release of PGF2α were studied in vitro on isolated uteri from rats on day 19–20 of pregnancy that had been incubated in Krebs buffer, pH 7.4, at 37°C. The concentration of PGF2α in the media was measured using specific radioimmunoassays. It was found that the decidual and myometrial oxytocin receptors exhibit different ligand specificities. Of the agonists tested, oxytocin and arginine-vasopressin stimulated PGF2α release in a dose-dependent manner. Arginine-vasopressin has only 3% of the uterotonic potency of oxytocin, but was found to have 16% of its PGF2α-releasing activity. [4-Threonine, 7-glycine]oxytocin, a highly potent and selective uterotonic oxytocin analogue, had no detectable prostaglandin-releasing activity at a dosage 30 times higher than oxytocin. However, 1-deamino-[8-d-arginine]vasopressin, a highly potent and selective antidiuretic arginine-vasopressin analogue, which has only 10% of the uterotonic activity of arginine-vasopressin, was as potent as arginine-vasopressin in prostaglandin-releasing activity. Of the oxytocin antagonists tested, it was confirmed that 1-penicillamine, 2-O-methyl-tyrosine, 4-threonine]ornithine-vasotocin and its close congener [1-penicillamine, 2-p-methyl-phenylalanine, 4-threonine]ornithine-vasotocin are partial oxytocin antagonists and that 9-desglycinamide-[1-(β-mercapto-β-β-cyclopentamethylenepropionic acid)2-O-methyl-tyrosine, 4-threonine]ornithine-vasotocin, [1-(β-mercapto-β-β-cyclopentamethylenepropionic acid)2-O-methyl-tyrosine, 4-threonine]ornithine-vasotocin and 1-deamino-penicillamine [2-O-methyl-tyrosine]ornithine-vasotocin are full oxytocin antagonists. The two partial oxytocin antagonists blocked the uterotonic action of oxytocin but had agonistic activity on decidual receptors, stimulating release of PGF2α. The full oxytocin antagonists blocked both the uterotonic and PGF2α-releasing actions of oxytocin. Thus, the myometrial and decidual oxytocin receptors have different ligand specificities for agonists and antagonists. We propose that the two uterine oxytocin receptor subtypes be designated as OT1a for the myometrial uterotonic receptors and OT1b for the endometrial or decidual prostaglandin-releasing receptors.
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