Mutations in animals have provided insight into many aspects of normal and pathological human physiology. This paper reports the discovery and initial characterization of a new mutant dwarf rat. The mutation, inherited as an autosomal recessive, arose spontaneously in a breeding colony of Lewis rats at the Medical Research Council Cellular Immunology Unit, Sir William Dunn School of Pathology, Oxford, U.K., in 1985 and the strain has now been established both in Oxford and at Mill Hill. Body growth in the mutant is retarded such that at 3 months of age both males and females weigh approximately 40% less than their normal litter-mates, and continue to grow at a slower rate. The mutants show a selective reduction in pituitary GH synthesis and storage (pituitary GH concentrations were approximately 10% of normal in males and 6% in females). The concentration of their anterior pituitary trophic hormones (LH, TSH, prolactin and ACTH) were within the normal range in dwarf animals. Exogenous GH treatment for 5 days resulted in an increase in growth rate from 1.5 +/- 0.3 to 3.9 +/- 0.4 g/day in male mutants, and 0.8 +/- 0.2 to 3.1 +/- 0.1 g/day in females. Longitudinal bone growth rates were more than doubled by this treatment from 49 +/- 5 to 100 +/- 10 micron/day in females and from 52 +/- 11 to 131 +/- 16 micron/day in males. Dot blot and Northern blot analysis of pituitary mRNA extracts revealed that the GH message in mutants was between 20 and 25% of normal, and that the GH transcript was of normal size.(ABSTRACT TRUNCATED AT 250 WORDS)

The oxytocin and prolactin responses to suckling were measured in 10 women in early (n=5) and established lactation (n-5). Oxytocin was released in a pulsatile manner during suckling in all women, but the response was not related to milk volume, prolactin response, or parity of the mother. In all 10 women plasma oxytocin concentrations increased three to 10 minutes before suckling began. In five women this occurred in response to the baby crying, in three it coincided with the baby becoming restless in expectation of the feed, while in two it corresponded with the mother preparing for the feed. There was no prolactin response to stimuli other than stimulation of the nipple associated with suckling.These results clearly indicate that the milk ejection reflex, with release of oxytocin, occurs in most women before the tactile stimulus of suckling. A second release of oxytocin follows in response to the suckling stimulus itself. Thus it is important that care is taken to protect breast feeding mothers from stress not only during suckling but also immediately before nursing, when conditioned releases of oxytocin will occur.

Young hypophysectomized rats were maintained with chronic indwelling i.v. cannulae attached via swivels to a multichannel pumping system programmed to deliver GH in a continuous or pulsatile pattern for several days. Continuous i.v. infusions of human GH for 5 days produced dose-dependent increases in body weight and tail length, without increasing food intake. A comparison of GH infusions by the s.c. or i.v. route showed that the direct i.v. route was threefold more effective. Pulsatile i.v. infusions of human or bovine GH at two doses (12 or 36 mu./day, eight pulses/day, 5-min duration, every 3 h) produced greater increases in body weight than continuous i.v. infusions of GH at the same daily dose. Continuous infusions of bovine GH produced a lower growth rate in the second of two consecutive 5-day treatment periods, whereas the responses to pulsatile GH did not diminish with time. Both body weight gain and long-bone growth were affected by the frequency of GH pulses; nine pulses per day were more effective than three pulses per day which in turn produced larger growth responses than one pulse per day. Keeping GH pulse frequency constant and varying pulse duration (4, 16 or 64 min) did not affect growth rates. In conclusion, long-term pulsatile i.v. infusions of GH mimic the endogenous secretory pattern, and are most effective when given at the physiologically appropriate pulse frequency.

SUMMARY1. The effects of adrenalectomy (3 weeks) and dexamethasone (3 h) treatment on the release of corticotrophin-releasing factor-41 (CRF-41), arginine vasopressin (AVP), oxytocin (OT), adrenocorticotrophin (ACTH) and corticosterone were studied in adult female Wistar rats.2. The animals were anaesthetized with sodium pentobarbitone which, as assessed by the effects on the circadian rhythm of plasma ACTH and corticosterone, appeared to be a better anaesthetic than either urethane or alphaxalone for studies on the hypothalamic-pituitary-adrenal system.3. Adrenalectomy increased the concentrations of ACTH in peripheral plasma and the output of CRF-41 and AVP into hypophysial portal plasma.4. Dexamethasone administered to adrenalectomized rats significantly reduced the concentration of ACTH in peripheral plasma and the amount of AVP released into portal plasma. However, dexamethasone did not affect the output of CRF-41 into portal blood.5. The output of OT into portal plasma was unaffected by either adrenalectomy or dexamethasone treatment.6. Dexamethasone administered to adrenalectomized rats reduced significantly the ACTH response to 7. These results show that the feed-back action of glucocorticoids is mediated by two mechanisms. The increased release of ACTH and corticosterone which follows adrenalectomy is produced predominantly by an increased release of both CRF-41 and AVP into hypophysial portal blood. The intermediate negative feed-back of glucocorticoids is produced by a reduction in the output of AVP but not CRF-41 into portal blood-and, as well, by a significant reduction in the responsiveness of the anterior pituitary gland to CRF-41.

We have studied the rebound secretion of GH following short-term somatostatin (SS) infusions in conscious rats, using an automatic sampling system for withdrawing frequent microsamples of blood. Intravenous infusions of SS (5-50 micrograms/h per rat) inhibited spontaneous GH secretion, but when SS was withdrawn there was a large burst of rebound GH secretion. A sub-anaesthetic dose of urethane reduced such rebound bursts of GH, suggesting a hypothalamic involvement in rebound GH secretion. Passive immunization with an antibody against rat GH-releasing factor (GRF) attenuated the rebound GH secretory response to the withdrawal of an SS infusion (GH concentration during rebound secretion was 26 +/- 21 micrograms/l vs 475 +/- 127 micrograms/l (mean +/- S.E.M.), after 0.5 ml anti-GRF serum or non-immune serum respectively). The inhibition of GH rebound secretion was related to the dose of anti-GRF serum administered. Intravenous infusions of human GH (20-100 micrograms/h per rat) also reduced the size of the rebound GH secretion following SS withdrawal, in both male and female rats. We suggest that the rebound GH secretion that follows SS withdrawal in vivo is caused mainly by a hypothalamic release of GRF. Exogenous GH inhibits SS-induced rebound GH secretion in the conscious rat, possibly by inhibiting hypothalamic GRF release.