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The content of vasopressin, oxytocin and their related neurophysins was measured in the hypothalamus and pituitary gland of mid-trimester human fetuses. Vasopressin was present in both tissues approximately 3–4 weeks before oxytocin. The levels of the hormones in the pituitary gland increased 1000-fold over the next 3–4 months. During this time, the very high vasopressin/oxytocin ratio gradually decreased but did not reach unity in the period studied. In contrast, both the vasopressin-associated neurophysin and the oxytocin-associated neurophysin appeared in the pituitary gland at the same gestational age and showed the same exponential increase with fetal age. Lower levels of the neurophysins and the nonapeptides were found in the hypothalamus and the levels increased more slowly with fetal age. Our results suggest that the high vasopressin/oxytocin ratios observed in fetal life are due to differences in the rate of maturation of the hormone precursor, rather than to differences in the rate of de-novo synthesis.
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Oxytocin and bovine neurophysin I (bNpI) were estimated by radioimmunoassay in jugular vein plasma which was collected continuously from 18 bulls. No release of peptides was observed during successive matings with a cow in oestrus or during successive mountings on a cow with ejaculations into an artificial vagina. Stimulation with an electro-ejaculator or, to a smaller extent, massage of the seminal vesicles and ampullae per rectum caused an increase of oxytocin accompanied by a release of bNpI. It is speculated that the release of these peptides is due to stimulation of afferent pelvic nerves in the rectal wall. Basal molar ratios of bNpI/oxytocin in the plasma were highly variable, often showing a large excess of either bNpI or oxytocin. After the onset of peptide release induced by stimulation, molar ratios approached 1:1. This might indicate that hormone release is by exocytosis. Basal bNpI does not provide a good reflection of the oxytocin level.
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Abstract
We have recently provided evidence for the desensitization of oxytocin receptors in human myometrial cells. In the present study, we have investigated the possible mechanisms by which oxytocin (OT) might regulate OT receptor density. The steady state level of OT binding in cultured myometrial cells was 220 × 103 binding sites/cell, but this was time-dependently reduced to 27 × 103 sites/cell by exposure to OT for up to 20 h. Similarly, OT exposure decreased the binding of OT to cell membranes. In contrast, Western blotting data showed that the total amount of OT receptor protein was not affected by OT treatment for up to 48 h. Flow cytometry experiments demonstrated that OT receptors are not internalized during prolonged exposure of the cells to OT. However, RNase protection assays and Northern analysis showed that OT receptor mRNA was reduced by OT treatment to reach a new low steady state level with a time course similar to that of the disappearance of cell surface OT binding sites. Possible mechanisms involved in mRNA down-regulation include transcriptional suppression and destabilization of mRNA by RNA binding proteins.
Journal of Endocrinology (1997) 154, 7–18
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ABSTRACT
An oxytocin-like peptide is present in the interstitial cells of the testis, and testicular concentrations of oxytocin have been shown to increase seminiferous tubule movements in vitro. We have used the drug ethan-1,2-dimethanesulphonate (EDS), which depletes the Leydig cell population of the adult rat testis, to examine further the relationships between the Leydig cell, testicular oxytocin and tubular movements. Adult rats were injected i.p. with a single dose of EDS (75 mg/kg) or of vehicle (25% dimethyl sulphoxide). Histological study 3 and 10 days after treatment with EDS showed a reduction in the number of interstitial cells, and levels of oxytocin immunoreactivity were undetectable by radioimmunoassay. Immunostaining revealed very few oxytocin-reactive cells. Spontaneous contractile activity of the seminiferous tubules in vitro was also dramatically reduced, but could be restored by the addition of oxytocin to the medium. Four weeks after EDS treatment, the interstitial cells were similar to those in the control animals both in number and in immunostaining; immunoassayable oxytocin was present and tubular movements were normal. The EDS effect, seen at 3 and 10 days, was not altered by daily treatment with testosterone. However, repopulation of the testes with oxytocin-immunoreactive cells was not seen until 6 weeks in the testosterone-treated animals.
We suggest that the Leydig cells are the main source of oxytocin immunoreactivity in the testis and that this oxytocin is involved in modulating seminiferous tubule movements and the resultant sperm transport. The results also imply that testosterone does not play a major role in controlling tubular activity in the mature rat.
J. Endocr. (1987) 112, 311–316
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ABSTRACT
Binding of [3H]oxytocin to purified myometrial plasma membranes was unaffected by continuous infusion of bradykinin over 5 days in rats pretreated with oestradiol 2 days before collection of tissue. In contrast, oxytocin treatment resulted in a 76% decrease in maximal binding of [3H]oxytocin and thereby in oxytocin receptor concentration without affecting the dissociation constant. The K M value (molar concentration giving half maximal contraction) of isolated uterine strips stimulated with oxytocin was increased and maximal contractile responses were reduced following oxytocin infusions.
The binding of [3H]bradykinin to purified plasma membranes was influenced by treatment with both oxytocin and bradykinin. Bradykinin infusions down-regulated the bradykinin receptor concentration by 19%, while the receptor affinity remained unchanged. Maximal contraction (Emax) values of isolated strips stimulated with bradykinin exhibited a slightly attenuated response and K M values were significantly enhanced. Long-term treatment with oxytocin down-regulated myometrial bradykinin receptors by 31%. In addition, oxytocin infusions caused Emax to decrease and K M to increase in experiments with isolated uterine strips stimulated with bradykinin.
It is concluded that the down-regulation of oxytocin and bradykinin receptors following prolonged exposure to oxytocin may result from changes in a common pathway for intracellular peptide receptor processing. Likewise, the increased K M values of isolated myometrial strips (despite unchanged dissociation constants) suggest that prolonged oxytocin treatment affects the coupling between receptor activation and contractile response.
J. Endocr. (1988) 118, 81–85
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SUMMARY
The oxytocin-inactivating activity (OIA) of rat uterus homogenates was studied in intact animals and in animals with bilateral intrauterine devices (IUD). In another series of experiments the OIA of the rat uterus was related to the mast cell count of uteri from intact rats and from rats with bilateral intrauterine devices. The OIA of the homogenates was significantly higher at oestrus than at dioestrus. No such increase was observed in homogenates from rats at oestrus with bilateral IUD's. The IUD caused an increase in the mast cell population at oestrus and the increase in mast cell counts observed in uterine homogenates of intact rats at dioestrus was not observed in the presence of a device. No correlation between the OIA of uterine homogenates and the mast cell population was observed in animals with or without IUD at oestrus or dioestrus.
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ABSTRACT
In urethane-anaesthetized ovariectomized rats, injection of porcine relaxin (7·5 and 15 μg/kg, i.v.) caused a sustained increase in circulating plasma oxytocin and vasopressin concentrations; 10 μg relaxin/rat i.v. produced a smaller but significant increase in plasma oxytocin concentration in conscious ovariectomized rats. A significant increase in oxytocin concentration and inhibition of the spontaneous milk-ejection reflex was also seen in anaesthetized (ovary intact) lactating rats following injection of relaxin (7·5 μg/kg, i.v.). To investigate whether relaxin acts by increasing the electrical activity of oxytocin neurones or by facilitating stimulus-secretion coupling in the pituitary, the electrical activity of neurones in the supraoptic nucleus was recorded in urethane-anaesthetized lactating rats and in ovariectomized rats. Porcine relaxin (10 μg/rat, i.v.) increased the firing rate of both oxytocin and vasopressin neurones in the supraoptic nucleus in lactating rats. The response to relaxin was unaffected by subsequent injection of naloxone (1 mg/kg, i.v.). Oxytocin neurones were also activated by injection of relaxin (10 μg/rat) into ovariectomized rats. Combining the electrophysiological data, the neuronal activation following relaxin was significantly correlated with the level of spontaneous activity prior to relaxin injection. The results show that relaxin acts centrally to increase circulating plasma oxytocin and vasopressin concentrations by an opioid-independent mechanism.
Journal of Endocrinology (1992) 132, 149–158
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ABSTRACT
The effect of RU486, a synthetic progesterone receptor antagonist, on basal uterine prostaglandin (PG) release and release in response to oxytocin injection has been investigated in late-pregnant sheep (days 135–140 of gestation). Fifteen hours after i.m. injection of RU486 (50 mg; n = 5) or vehicle alone (n = 4), bolus injections of oxytocin (50, 500 and 5000 mU) were administered via a uterine artery ipsilateral to the pregnant uterine horn at 2-hourly intervals. Uteroovarian vein concentrations of 13,14-dihydro-15-keto PGF2α (PGFM) and PGE2 were determined before and during oxytocin stimulation. Basal concentrations of both PGFM and PGE2 were significantly (P < 0·001) increased in ewes 15 h after RU486 administration compared with ewes receiving vehicle alone. Concentrations of PGFM, but not PGE2, increased significantly (P < 0·001) following injection of each dose of oxytocin in both treated and untreated animals. The response to oxytocin, measured both as the area under the curve and as the peak height of PGFM release, was significantly (P <0·05) greater in RU486-treated ewes. There was no significant effect of oxytocin on the area or peak height of PGE2 response in either RU486-treated or control animals. These results demonstrate that treatment of late-pregnant ewes with RU486 results in an increase in basal uterine PGFM and PGE2 as well as oxytocin-stimulated PGFM release.
Journal of Endocrinology (1992) 134, 353–360
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We have recently uncovered the presence of an oxytocin system in the heart and found that oxytocin is a physiological regulator of atrial natriuretic peptide (ANP), a diuretic, natriuretic and vasodilator cardiac hormone. However, dynamic changes in these systems during gestation, when mechanisms of volume and pressure homeostasis are altered, are not clear. Accordingly, ANP, oxytocin and oxytocin receptors were evaluated in rat hearts and plasma at three stages of gestation (7, 14 and 21 days) and at 2 and 5 days postpartum. Compared with non-pregnant controls, plasma ANP was elevated in mid-gestation, but significantly decreased at term (21 days), to increase again postpartum. Right and left atrial ANP mRNA levels were not altered throughout gestation but increased by 1.5- to 2-fold postpartum (P<0.01). At term, ANP content in right (8.7+/-1.2 vs 12.7+/-1.1 micro g/mg protein, P<0.04) and left (3.5+/-0.6 vs 8.5+/-2.0 micro g/mg protein, P<0.01) atria increased. These findings imply that decreased plasma ANP at term results from inhibition of release rather than decreased synthesis. In parallel, oxytocin, a stimulator of ANP release, decreased in left atria at day 7 to 50% of non-pregnant levels and remained low throughout gestation. Oxytocin receptor mRNA increased in left atria at 7 and 14 days of gestation by 2- and 5-fold respectively, but decreased at 21 days to lower than non-pregnant levels to increase again (3-fold) postpartum. The changes in oxytocin receptor expression at term and postpartum paralleled oxytocin receptor protein determined by Western blot. These results imply that pregnancy is associated with dynamic changes in the cardiac oxytocin system (peptide and/or receptors), which may influence natriuretic peptide release. Together, these peptides would act on their receptors in the heart, vasculature and kidneys to maintain vascular tone and renal function throughout gestation and postpartum.
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ABSTRACT
The influence of treatment with oestradiol on the effects of the uterine relaxants, relaxin, salbutamol (an agonist at β2-adrenoceptors) and cromakalim (a potassium channel opener) and their interactions with the uterine stimulant oxytocin were investigated in vivo in the ovariectomized rat. Oestradiol benzoate (0·4 μg/kg per day) significantly increased sensitivity to cromakalim as an inhibitor of spontaneous uterine contractions compared with vehicle-treated rats by approximately threefold. The same dose of oestradiol benzoate had no effect on uterine sensitivity to salbutamol. Previous studies have shown that this dose of oestradiol benzoate produces a twofold increase in uterine sensitivity to relaxin as an inhibitor of spontaneous contractions. Oestradiol influenced the ability of relaxin to inhibit oxytocin-stimulated uterine contractions. In corn oil-treated rats, uterine responses to relaxin were markedly reduced during oxytocin infusion compared with responses to relaxin before oxytocin; the maximum obtainable response to relaxin was less than 50% inhibition. In oestradiol-treated rats, uterine sensitivity to relaxin during oxytocin infusion was similar to that observed against spontaneous contractions. Cromakalim was able to inhibit uterine contractions during oxytocin infusion in both corn oil- and oestradiol-treated rats, uterine sensitivity to cromakalim being similar in the absence and presence of oxytocin for both hormone treatment groups. Salbutamol was also able to inhibit uterine contractions during oxytocin infusion in both corn oil- and oestradiol-treated rats. Oestradiol treatment increased the potency of salbutamol as an inhibitor of oxytocin-stimulated uterine contractions compared with corn oil treatment by 3·5-fold. The interaction of oestradiol and relaxin during late pregnancy may be important for attenuation of the myometrial response to stimulants.
Journal of Endocrinology (1992) 135, 29–36
