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P R Riley, D R E Abayasekara, H J Stewart, and A P F Flint


The entire coding region of an ovine endometrial oxytocin receptor (OTR) cDNA was generated by PCR, subcloned into the SV40 major late promoter expression vector pSVLJ and transiently expressed in Cos-7 cells. A specific OTR antagonist, 125I-labelled d(CH2)5 [Tyr(Me)2,Thr4,Tyr-NH2 9]-vasotocin (OTA), was used to describe the binding kinetics of the expressed receptor which had a K d of 4·5 nm and Bmax of 2·4 nm/mg protein (6·8 × 105 receptor molecules/transfected cell). The functional properties of the expressed OTR were determined by measuring oxytocin-induced phosphoinositide (PI) hydrolysis. Oxytocin increased PI turnover in OTR transfected cells fourfold in excess of residual endogenous activity, and stimulated phospholipase C (PLC) activity in a dose- and time-dependent manner, confirming that the expressed OTR cDNA was functional. Arginine vasopressin also stimulated PI turnover in a dose-dependent manner; thresholds of responses to oxytocin and arginine vasopressin were 10−9 m and 10−7 m respectively. OTA did not increase PI turnover and competitively inhibited the oxytocin-induced response. Direct activation of the pathway by aluminium fluoride and guanosine (3′-Othio)-triphosphate (GTPγS) confirmed that the OTR was G-protein linked. Co-incubation of GTPγS with oxytocin shifted the PI-response threshold from 10−7 m to 10−9 m and significantly increased the level of response, suggesting that maximum PI turnover was agonist-dependent. The G-protein involved in mediating the signal transduction pathway was pertussis toxin-insensitive and, therefore, probably a member of the Gq subfamily. The PLC inhibitor, U73122, had no effect on oxytocin-induced PI turnover, consistent with the response in endometrial tissue. These data suggest that the signalling pathway mediated by expressed OTR is similar to that attributed to OTR occupancy in ovine endometrium.

Journal of Endocrinology (1996) 149, 389–396

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R J Windle, J M Judah, and M L Forsling


The renal effects of arginine vasopressin and oxytocin were studied in the conscious unrestrained rat infused with 0·077 m NaCl. Peptides were infused at rates of 24 and 160 pmol/min (vasopressin) or 30 and 200 pmol/min (oxytocin) either alone or as a combination of the two lower or two higher doses. The rates of infusion were selected to give ratios of oxytocin:vasopressin similar to those seen in the plasma of euhydrated and dehydrated rats.

Vasopressin produced dose-dependent antidiuretic and natriuretic responses, the natriuresis commencing after 15–30 min infusion. Oxytocin produced dose-dependent diuretic and natriuretic responses, the natriuresis commencing within the first 15 min of infusion. Combined infusion of vasopressin and oxytocin produced dose-dependent antidiuretic responses which were comparable to those seen with vasopressin alone. The natriuretic response from combined infusion at the higher rate appeared to have the greater magnitude for individual 15-min periods of the vasopressin response combined with the longer duration of the oxytocin response. Although the total natriuretic response was therefore greater, this difference failed to reach significance.

Only the higher rates of infusion of vasopressin and oxytocin significantly increased the clearance of sodium, by 53 ± 23 and 62 ± 18% and glomerular filtration rate (GFR) by 23 ± 4 and 23 ± 4% respectively. The clearance of sodium during the combined hormone infusion was significantly greater (109 ± 21%), while the rise in GFR at 23 ± 5% was comparable to that seen when each hormone was given separately. Both fractional excretion of sodium and potassium excretion were also significantly elevated by this combined infusion, suggesting an additional tubular component to the response. Although no synergistic effect of neurohypophysial hormones on the antidiuresis was found in the conscious rat, they may act together to promote sodium excretion

Journal of Endocrinology (1995) 144, 441–448

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Oxytocin has been assayed in the jugular vein blood of goats during parturition; for comparison a few measurements were also made during pregnancy. The hormone was extracted from blood plasma by gel filtration, followed by lyophilization and then assayed in the lactating guinea-pig by the increase in intramammary pressure after intra-arterial injection.

No oxytocin could be detected in the blood during pregnancy and it was found in only one of eight goats studied during the first stage of labour. The hormone was present in appreciable quantities in blood taken during the second stage of labour, and in general, the concentration rose to a maximum when the head presented. In cases of twin births oxytocin was usually present in the blood during the birth of the second kid but at a concentration lower than during delivery of the first. After expulsion of the kid the blood oxytocin titre diminished rapidly, suggesting that secretion of oxytocin ceased as soon as the kid was born. In three experiments the total release of oxytocin during a considerable portion (2·7–11·0 min.) of the second stage labour was estimated as 223–726 m-u.

The results are consistent with the view that oxytocin is not essential for the induction of labour. Rather the hormone is released in response to stimuli arising from distension of the vagina and vulva, and by virtue of its contractile effect on the uterus assists parturition.

The half-life of intravenously injected oxytocin in the lactating goat was found to be 1 min. 22 sec. After storage of lyophilized blood extracts at −15° for 5 months milk-ejection activity had declined by only 27%.

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At 4°, the activity of exogenous 8-arginine vasopressin in rat plasma decreased to 50% in 2 days, whereas there was no loss of oxytocin under the same conditions after 3 days. At 37°, oxytocin was not inactivated in 9 hr., whereas 50% of 8-arginine vasopressin was lost in 2 hr.

Forty per cent of exogenous oxytocin in rat plasma was unable to pass through a cellophane (Visking 8/32 in.) membrane, when subjected to a pressure of 100 torr for 18 hr.

In rats under pentobarbitone anaesthesia, progressive haemorrhage of more than 2·0 ml./100 g. induced a secretion of both oxytocin and 8-arginine vasopressin, to produce maximum concentrations of 450 and 700 μ-u./ml., respectively, in the carotid plasma.

In the intact rat (weighing 200–250 g.) anaesthetized with pentobarbitone, 50% of oxytocin in the circulation disappeared within 2 min. after stopping an i.v. infusion of 250–6000 μ-u./100 g./min. The half-time was increased to 4 min. by sham operation, and to 6 or 7 min. by occluding either the renal, or the portal, coeliac and mesenteric vessels. In non-lactating animals, the half-time was 8 min. after clamping both the renal and splanchnic vessels, whereas it was 6 min. in the lactating rat, under the same conditions.

The apparent volume of distribution of oxytocin was 7·3 ml./100 g. in intact rats, and 10–13 ml./100 g. after operation.

The plasma clearance of oxytocin was unaltered in the sham-operated rat, but it decreased after the operative procedures.

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J J Evans, S J Hurd, and D R Mason


Although GnRH is believed to be the primary secretagogue for LH, oxytocin has also been shown to stimulate LH release from the anterior pituitary. We investigated the possibility that the two secretagogues interact in the modulation of LH release. Anterior pituitaries were removed from adult female rats at pro-oestrus, and tissue pieces were pre-incubated in oxytocin for 3 h prior to being stimulated with 15 min pulses of GnRH. LH output over the 1 h period from the beginning of the GnRH pulse was determined. Control incubations were carried out in the absence of oxytocin, and background secretory activities without GnRH stimulation were also determined.

Tissue which was pre-exposed to oxytocin (0·012–1·25 μm) had an increased LH response to GnRH (1·25 nm). The increase was larger than the sum of the LH outputs obtained with oxytocin and GnRH separately, revealing that oxytocin synergistically enhanced LH secretion elicited by GnRH (P<0·05; ANOVA). If stimulation by GnRH was delayed for 2 h after incubation with oxytocin, an increase in LH secretion was still observed, indicating that oxytocin-induced modulation did not rapidly disappear. Oxytocin pre-incubation was observed to result in an increase of maximal GnRH-induced LH output (P<0·001; t-test), as well as an increase of intermediate responses.

The LH response of the anterior pituitary to subsequent pulses of GnRH was modified by the self-priming process. The effect of oxytocin pretreatment on the response of primed tissue to GnRH was also investigated. It was found that pre-incubation in oxytocin also enhanced the LH response of primed tissue to GnRH.

The study has revealed that oxytocin increases the LH output of anterior pituitary tissue in response to GnRH. The effect occurs on both GnRH-primed and unprimed tissues. The results suggest that oxytocin has the potential to regulate the dynamics of the pro-oestrous LH surge.

Journal of Endocrinology (1995) 145, 113–119

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T. Higuchi, K. Uchide, K. Honda, and H. Negoro


Developmental changes in levels of oxytocin in the blood and the pituitary gland and in oxytocin responses to oxytocin-releasing stimuli were investigated in the rat from the fetus close to term to the 40-day-old young adult. The oxytocin content of the pituitary gland rose gradually from fetuses of 21 days of gestation to 40-day-old rats. Pituitary oxytocin levels expressed in terms of body weight also increased up to day 25 after birth and declined slightly thereafter. In contrast, serum concentrations of oxytocin increased from day 21 of pregnancy up to day 5 after birth but were stable thereafter. Oxytocin levels in both blood and the pituitary gland were equal in 23-day-old fetuses and 1-day-old infants born on day 22 of pregnancy. There was no difference in serum and pituitary oxytocin levels in newborn pups and unborn littermates of day 22 or 23 of gestation. The i.p. injection of hypertonic saline induced a significant increase in serum oxytocin levels on day 5 and later, but no effect in the fetus on day 22 of gestation and in the 1-day-old infant. The responsiveness to the osmotic stimuli increased after 5 days of age. The i.p. injection of diethyl-dithiocarbamate, a noradrenaline synthesis inhibitor, or phenobarbitone was effective in raising blood oxytocin levels only in rats older than 10 and 20 days of age respectively. These findings, that a gradual increase in oxytocin levels in both blood and the pituitary gland without an apparent increase in its release and the absence of a pituitary response to oxytocin-releasing stimuli during the perinatal period, do not support a role for fetal oxytocin in the initiation of labour in the rat.

J. Endocr. (1985) 106, 311–316

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Two experiments were performed to study the effects of bromocriptine and α-ergocryptine on oxytocin secretion in lactating rats. In both experiments, after overnight separation from their litters, rats were injected with either vehicle alone or ergot alkaloid plus vehicle; 4 h later the litters were returned.

In the first experiment the mothers were conscious. Treatment did not affect suckling behaviour, number of stretch reactions or litter weight gain in the first 30 min. Oxytocin injection before the second 30 min period of suckling caused no extra milk to be obtained. In the second experiment the mothers were anaesthetized with ethyl carbamate (1·1 g/kg body weight) at the time of the ergot alkaloid or vehicle injection. Changes in intramammary pressure were recorded during suckling. Ergot alkaloids altered neither the number of milk ejections caused by suckling, nor the proportion of milk ejections equivalent to 0·2 mu. or more oxytocin.

In both experiments treatment with ergot alkaloids suppressed secretion of prolactin. It is concluded that (a) in suppressing lactation, bromocriptine and α-ergocryptine do not inhibit oxytocin secretion as well as prolactin secretion, and that (b) prolactin secretion is not a necessary concomitant of oxytocin secretion.

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R. Claus and D. Schams


Oxytocin concentrations were measured radioimmunologically in sows on the day of standing oestrus over a 6-h period (controls, n=6) or 1 h before and 5 h after mating (n=5) or transcervical infusion of either 100 ml saline (0·9% (w/v) NaCl, n=7) or saline plus 10 μg oestradiol (simulation of seminal oestrogens, n=5).

In the controls, oxytocin was low, at around 1·0 pmol/l, throughout the investigation period. Similarly, saline infusion did not lead to a noticeable change in oxytocin concentrations in six out of seven sows. In one sow, however, infusion led to a maximum of 86 pmol/l at 1 min after infusion. Oestradiol led to no immediate increase in oxytocin concentrations. Later in the post-treatment period (2–5 h) they were only slightly increased (1 pmol/l vs 3 pmol/l). All mated sows reacted with a rapid and clear increase in oxytocin. Maximal concentrations (42·0±5·1 pmol/l; mean ± s.e.m.) appeared 2 min after the onset of ejaculation. Clearly increased concentrations were found for 40 min. It was concluded that mating specifically leads to a rise in oxytocin, probably due to both mechanical and pheromonal stimuli provided by the boar.

Journal of Endocrinology (1990) 126, 361–365

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S. A. Jones and A. J. S. Summerlee


The effects of chronic infusion of porcine relaxin on oxytocin release were studied in lactating rats. Infusion of relaxin (4·2 μg/h for either 4 or 6 days) suppressed reflex milk ejection and reduced litter weight gain for 48 h compared with saline-infused controls. After 2 days, neither the rate of growth nor the frequency of milk ejection were significantly different from controls. For 24 h after the infusion of relaxin ended, litters gained weight more quickly than controls but there was no difference seen in the frequency of milk ejection. The effects on oxytocin release of stopping an infusion of relaxin after 3 days were investigated. There was a significant (P <0·01) rise in plasma oxytocin (up to 90 pmol/l) 30 min after the infusion was stopped, followed by a sustained rise in intramammary pressure. Treatment of relaxin-infused rats with naloxone (0·1 mg/kg) when the infusion was halted caused a more rapid release of oxytocin (within 2 min), a greater release of oxytocin (up to 140 pmol/l) and a prolonged rise in intramammary pressure.

J. Endocr. (1987) 114, 241–246

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R. J. Windle and M. L. Forsling


Oxytocin concentrations in the plasma, pituitary and hypothalamus of female rats were determined in the morning and evening over the 4-day oestrous cycle. Vasopressin concentrations were also determined to allow calculation of the ratios of the two hormones. The results were compared with those from male rats. Plasma oxytocin concentrations were significantly higher in the evening than in the morning on the day of oestrus. Although the evening concentration achieved was similar on each day of the cycle, morning plasma oxytocin concentrations showed a progressive rise from oestrus to pro-oestrus so that no significant diurnal increases were observed on the other days of the cycle. Vasopressin concentrations in the plasma were also seen to increase over the days of oestrus, dioestrus day 1 and dioestrus day 2. On pro-oestrus the plasma concentrations of vasopressin remained unchanged. The ratio of oxytocin:vasopressin fell during the light hours of the cycle. The hypothalamic content of both hormones showed a rise during the hours of daylight parallel to that seen in the plasma, whereas the pituitary content fell over the same period. The diurnal pattern of hormone release observed in male rats was similar to that in females at oestrus. However, the plasma oxytocin concentrations were significantly higher in the male.

The plasma clearance rate of vasopressin did not vary significantly during the oestrous cycle. However, the plasma clearance rate for oxytocin did show significant variation, being highest on dioestrus day 1 and lowest on dioestrus day 2.

Journal of Endocrinology (1993) 136, 305–311