Specific binding of tritiated oxytocin to uterine receptors of pregnant rats increases dramatically at term and is maximal during labor. In mammary glands the increase in binding is gradual, reaching a maximum during the lactation period. Concomitant changes in the sensitivity of the uterus and mammary gland to oxytocin indicate that the receptor concentration is of functional significance. Oxytocin receptors, therefore, may regulate the response of the target organs to circulating oxytocin and thereby control the onset of labor and lactation. Ovarian steroids participate in the regulation of oxytocin receptors in a manner as yet unclarified.
Marked changes in the uterine binding of oxytocin (OT) occur in rats at the time of parturition or after treatment of ovariectomized rats with estrogen or progesterone. To ascertain that these binding sites represent the biological receptors for OT, we measured the uterine response to OT in various groups of rats in which specific OT binding was also determined. Intact pregnant rats and rats ovariectomized on day 20 of gestation and treated thereafter with oil, estradiol benzoate (5 micrograms/24 h), progesterone (5 mg/24 h), or estradiol and progesterone together had indwelling balloons inserted on day 20 for the recording of uterine response to either iv bolus injections or iv infusions of OT. The uterus was removed 24-48 h after balloon insertion, and OT binding to the particulate fraction as well as nuclear estrogen and cytosolic estrogen receptor concentrations were determined. An inverse correlation (r2 = 0.758) was found between the concentration of OT-binding sites and the threshold dose of OT, and a linear correlation was found between the concentration of binding sites and the uterine activity induced by OT infusion (r2 = 0.852). We conclude, therefore, that the high affinity (Kd, 1-2 nM) binding sites for OT represent the physiological receptors. The concentration of these sites increased progressively during estrogen treatment. Progesterone completely inhibited this estrogen-induced rise. After ovariectomy, there was a modest, but significant, increase in OT receptor concentration which also was prevented by progesterone. The increase in OT receptor concentration was correlated with the estrogen receptor concentration in intact pregnant and estrogen-treated ovariectomized animals, but not in the other groups of animals. The apparent affinity of the receptors for OT was not significantly affected by hormone treatment. We conclude that the concentration of receptors is a major factor controlling the uterine responsiveness to OT, and that the receptor concentrations are regulated by ovarian hormones in a manner related to estrogen receptor activation. In addition, estrogen appeared to enhance the coupling of OT receptor occupancy to the tissue response to OT.
Rat myometrium exhibited a marked rise in the concentration of oxytocin (OT) receptors during parturition. The elevation began several hours before labor, was maximal during labor, and declined several hours later. In the perinatal period, the change in OT receptor concentration was proportional to the ratio of plasma estradiol to progesterone levels. Several hours before the increase in OT receptor concentration, there was a proportional increase in estrogen receptor concentration in both the cytosol and nuclear fractions of the myometrium. In view of the known action of estrogens in increasing the concentration of OT receptors in rat uterus, we propose that the following sequence of events occurs in the initiation of labor in the rat. The decline in serum progesterone permits estradiol to stimulate the synthesis of estrogen receptors in the myometrium. This increased concentration of estrogen receptors and their occupancy by estradiol stimulates the appearance of more OT receptors, which then trigger labor by interacting with circulating OT.
It has been postulated that intrauterine volume plays a role in the timing of parturition. In previous studies we found that the onset of parturition in the rat was associated with marked increases in the concentrations of receptors for estrogen and oxytocin in the myometrium. To determine the effects of intrauterine volume on the concentrations of these myometrial receptors, we compared receptor levels in gravid and nongravid uterine horns from unilaterally pregnant rats at or near the time of parturition. Myometria from gravid horns contained substantially greater concentrations of DNA and protein per horn than did myometria from the contralateral nongravid horns. The amounts of receptors per horn for estrogen in the nuclear and cytosol fractions and for oxytocin were 7.5, 5.2, and 4.5 times greater, respectively, in myometria from gravid horns. However, the concentration of receptors per cell was the same in gravid and nongravid horns at or near parturition. These results suggest that uterine stretch causes hyperplasia and hypertrophy of the myometrium, indicative of more DNA and protein per gravid horn than nongravid horn. The sharp rise in concentration per cell of receptors for estrogen and oxytocin occurring about the time of labor, however, appears to be induced by hormonal and not physical factors.
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