Biomedical subjects

I C Robinson

Publications and source records attributed to I C Robinson.

At least 91 records · Page 5Linked to original sources

PubMed1990

Sex difference in growth hormone feedback in the rat.

Growth hormone inhibits its own secretion in animals and man but the mechanism for this inhibition is unclear: both stimulation of somatostatin release and inhibition of GH-releasing factor (GRF) release have been implicated. We have now studied the GRF responsiveness of conscious male and female rats under conditions of GH feedback induced by constant infusion of exogenous human GH (hGH). Intravenous infusions of hGH (60 micrograms/h) were maintained for 3 to 6 h whilst serial injections of GRF(1-29)NH2 (0.2-1 microgram) were given at 45-min intervals. The GH responses were studied by assaying blood samples withdrawn at frequent intervals using an automatic blood sampling system. We have confirmed that male and female rats differ in their ability to respond to a series of GRF injections; female rats produced consistent GH responses for up to 13 consecutive GRF injections, whereas male rats showed a 3-hourly pattern of intermittent responsiveness. In female rats, multiple injections of GRF continued to elicit uniform GH responses during hGH infusions, whereas hGH infusions in male rats disturbed their intermittent pattern of responsiveness to GRF, and their regular 3-hourly cycle of refractoriness was prolonged. We suggest that this sex difference in GH feedback may be due to GH altering the pattern of endogenous somatostatin release differentially in male and female rats. Such a mechanism of GH autofeedback could be involved in the physiological control of the sexually differentiated pattern of GH secretion in the rat.

Animals↗

PubMed1990

Pubertal development and testicular function in the male growth hormone-deficient rat.

The pubertal development of a novel GH-deficient mutant, the dwarf rat, has been evaluated. The establishment of normal spermatogenic function within small testes suggests that GH plays no role in spermatogenic function during puberty and adult life. However, a reduction in testicular size may reflect a reduced Sertoli cell population, suggesting that GH may be of importance in prepubertal testicular development. Furthermore, marked differences between the homozygous dwarf rat and homozygous GH-deficient mouse mutants (e.g. Snell, Ames, pygmy and little mutants) have been demonstrated. It would appear that the GH deficiency in the rat mutant is far more specific for GH than those hitherto described in the mouse. In contrast to Snell dwarf mice mutants, pituitary and serum concentrations of FSH and LH are normal throughout pubertal development in the dwarf rat. Both spermatogenic function and seminal vesicle function develop normally, whilst in Snell dwarf mice spermatogenic function develops late in life and seminal vesicles remain infantile. Serum and testicular concentrations of androgen are also normal in dwarf rats. Homozygous dwarf rats have been shown to be fertile in previous studies; however, our observations suggest that despite spermatogenesis being qualitatively and quantitatively normal when assessed histologically, reduced testicular size seen in dwarf rats would lead to a reduced daily sperm output in these animals. The dwarf rat represents a mutant in which the consequences of the selective depletion of GH may be studied on various endocrine systems. The reproductive axis appears to be only partially affected, at an early age, by GH deficiency.

Animals↗

PubMed1990

Growth hormone (GH) secretion in the dwarf rat: release, clearance and responsiveness to GH-releasing factor and somatostatin.

The new mutant GH-deficient dwarf (Dw) rat was used to study the effects of GH-releasing factor (GRF) or somatostatin (SRIF) on GH release. In anaesthetized adult Dw female rats, i.v. injections of GRF (0.031-2.0 micrograms) elicited a dose-dependent release of GH. Although the peak plasma GH responses to maximal GRF doses were much lower in adult Dw rats compared with normal rats of this strain (AS), the responses largely reflected their relative pituitary GH contents (140 +/- 17 micrograms vs 2.9 +/- 0.4 micrograms, AS vs Dw (means +/- S.E.M.), P less than 0.001). Except at 20 days of age, normal AS rats were more sensitive to GRF than Dw rats despite their larger body weight. Peak GH responses to injection of 31.25 ng GRF increased nine-fold in normal rats between 20 and 40 days, whereas the GH responses to this GRF dose diminished in Dw rats over this age range, and their pituitary GH content was only 2-5% of that of age-matched AS rats. Treatment with human GH (200 micrograms/day for 7 days) stimulated growth in 40-day-old Dw rats and slightly increased the GH response to a low dose of GRF. Basal GH levels in adult Dw animals were sevenfold lower than in AS rats (2.4 +/- 0.3 vs 17.6 +/- 3.3 micrograms/l P less than 0.001) and were further suppressed by i.v. infusion of SRIF (25 micrograms/h). As in normal rats, a rebound GH secretion occurred in Dw rats after stopping SRIF, which was blocked by injection of anti-GRF serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1989

Growth responses in a mutant dwarf rat to human growth hormone and recombinant human insulin-like growth factor I.

A new mutant GH-deficient dwarf rat has been used to study the effects of iv infusions of human GH (hGH) and recombinant human insulin-like growth factor I (hIGF-I). This animal has only about 5% of normal pituitary GH content, low circulating GH levels, and no regular GH surges. The defect seems to be specific for GH. Infusions of hIGF-I at 180 micrograms/day for 9 days elevated serum IGF-I concentrations significantly over those in the saline-infused controls (713 +/- 20 ng/ml vs. 395 +/- 31 ng/ml); hGH infusions did not raise IGF-I levels significantly (435 +/- 20 ng/ml). Gel filtration of serum samples showed that the high-dose hIGF-I infusions increased free IGF concentrations, without apparently altering the pattern of IGF-I binding whereas hGH infusions increased the amount of high mol wt IGF-I binding protein. Neither IGF-I nor hGH infusions affected the small amounts of rat GH present in the dwarf rat pituitary glands. Continuous iv infusions of hGH (200 mU/day for 9 days) stimulated body wt gain (2.1 +/- 0.2 g/day) and bone growth (96 +/- 9 microns/day) significantly compared to saline-infused dwarf rats (1.2 +/- 0.3 g/day and 43 +/- 3 microns/day). Infusions of hIGF-I at 180 micrograms/day produced a body wt gain (2.1 +/- 0.5 g/day) similar to that seen in the hGH-infused group but a significantly smaller stimulation of bone growth (63 +/- 3 microns/day). Infusion of a 5-fold lower dose of hIGF-I (36 micrograms/day for 9 days) had no effect on body wt or bone growth. Food intake was unaffected by either hGH or hIGF-I infusions. The pattern of tissue growth was affected differentially by hGH and IGF-I infusions that produced the same overall body wt gain. hGH induced a relatively proportional growth in most of the organs studied, whereas hIGF-I infusion at 180 micrograms/day stimulated a disproportionately greater growth of the kidney, adrenals, and spleen. In some of the animals, tissues were extracted for RIA of IGF-I; the amounts of IGF-I in the liver were similar in control, hGH, or IGF-I-infused animals, whereas kidney and adrenals from IGF-I infused animals contained larger amounts of immunoreactive IGF-I than did those tissues from hGH-treated rats. Thus, both hGH and hIGF-I can promote growth in the mutant dwarf rat, but they differ both quantitatively and qualitatively in their pattern of actions.

Animals↗

PubMed1989

Growth hormone and growth in diabetic rats: effects of insulin and insulin-like growth factor-I infusions.

The effects of streptozotocin-induced diabetes on weight gain, bone growth and GH secretion have been studied in conscious chronically cannulated male rats. In addition to the classic diabetic symptoms (hyperphagia, polydipsia, polyuria, glycosuria and hyperglycaemia), the slow body weight gain (0.95 +/- 0.5 compared with 2.63 +/- 0.5 g/day in non-diabetic controls) was associated with a reduction in bone growth (from 162 +/- 9 to 48 +/- 4 microns/day) and a reduced pituitary GH content (from 1.5 +/- 0.2 to 0.6 +/- 0.06 mg/gland). Serial blood sampling during the day or overnight showed that the normal male episodic GH secretory pattern was obliterated in the diabetic animals. The constant osmotic stimulation of hyperglycaemia and high fluid turnover was reflected in a significant reduction in pituitary oxytocin and arginine vasopressin (AVP) stores. Intravenous insulin infusions (67-1340 pmol/h for 4 or 7 days) caused a large initial weight gain (greater than 20 g in 2 days) followed by a slower increase, and stimulated tibial bone growth (to 100 +/- 16 and 126 +/- 8 microns/day after 4 or 7 days respectively). Insulin infusion for 7 days also increased pituitary GH content (to 1 +/- 0.15 mg/gland), and the normal episodic GH secretory pattern returned. Intravenous infusions of insulin which reduced, but did not completely normalize, blood glucose levels, allowed the resumption of growth and pulsatile GH secretion. Continuous infusion of recombinant human insulin-like growth factor-I (hIGF-I) at 1110 pmol/h for 54 h also caused a large initial rise in body weight in diabetic rats (17.1 +/- 1.6 compared with 7.5 +/- 2.8 g in saline-infused controls) due primarily to increased fluid retention. This effect of hIGF-I occurred without any significant changes in pituitary GH, AVP, oxytocin, blood glucose or bone growth over this short-term infusion, nor was there any obvious effect on spontaneous GH secretion, monitored over the entire infusion period. We conclude that the diabetic rat is not a good model to study growth stimulation by short-term insulin or IGF-I treatments because the insulin-like effects of these peptides obscure their specific growth-promoting activities in this model.

Animals↗

PubMed1988

Chronic intracerebroventricular morphine and lactation in rats: dependence and tolerance in relation to oxytocin neurones.

1. Acutely, opioids inhibit oxytocin secretion. To study the responses of oxytocin neurones during chronic opioid exposure, forty-five lactating rats were infused continuously from a subcutaneous osmotically driven mini-pump via a lateral cerebral ventricle with morphine sulphate solution from day 2 post-partum for 5-7 days; the infusion rate was increased 2- or 2.5-fold each 40 h from 10 micrograms/h initially up to 50 micrograms/h; controls were infused with vehicle (1 microliter/h, twenty-eight rats) or were untreated (eight rats). 2. Maternal behaviour was disrupted in 27% of the morphine-treated rats; in rats that remained maternal morphine did not affect body weight or water intake but increased rectal temperature by 0.82 +/- 0.14 degrees C (mean +/- S.E.M.) across the first 4 days. 3. Weight gain of the litters of maternal morphine-treated rats was reduced by 32% during 7 days, predominantly in the first day of treatment when milk transfer was also reduced. Observation of pup behaviour during suckling showed decreased frequency of milk ejections on only the second day of morphine treatment. Plasma concentration of prolactin after 6 days was similar in maternal morphine-treated and control rats, but reduced by 90% in non-maternal morphine-treated rats, indicating normal control of prolactin secretion by suckling in morphine-treated rats. 4. Oxytocin and vasopressin contents, measured by radioimmunoassay, in the supraoptic and paraventricular nuclei and in the neurohypophysis were similar between fourteen maternal morphine-treated, twelve vehicle-treated and eight untreated lactating rats; thus exposure to morphine did not involve increased production and storage of oxytocin. 5. Distribution of [3H]morphine infused intracerebroventricularly into six virgin female rats for 6 days was measured by scintillation counting of tissue extracts. Morphine concentration in the hypothalamus and neurohypophysis was 2.7 and 12.8 micrograms/g, respectively, and in blood plasma 0.75 micrograms/g. Tolerance was not due to failure of morphine infusion. In addition, naloxone (5 mg/kg s.c.) provoked typical withdrawal reactions ('wet dog' shakes, defaecation, burrowing) in lactating rats infused with morphine for 5 days. 6. Pups were suckled onto seven maternal morphine-infused and five vehicle-infused rats anaesthetized with urethane for recording of intramammary and arterial blood pressures after treatment for 5 days. The incidence and pattern of milk ejections, and mammary gland sensitivity to oxytocin were similar in the two groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

Effects of adrenalectomy and glucocorticoids on the peptides CRF-41, AVP and oxytocin in rat hypophysial portal blood.

1. 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 CRF-41. 7. These results show that the feed-back action of glucocorticoids is mediated by two mechanisms. The increased release of ACTH which follows adrenolectomy [corrected] 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.

Adrenalectomy↗

PubMed1988

Familial cerebellar ataxia and diabetes insipidus.

Two sisters are reported who both developed partial cranial diabetes insipidus in their 4th decade, followed by progressive cerebellar ataxia. This appears to be the first report of cerebellar ataxia and diabetes insipidus occurring together as a genetic entity.

Aged↗

PubMed1988

Neurohypophysial peptides in guinea pig hypophysial portal blood: equimolar release of the carboxyl terminal glycopeptide with arginine vasopressin.

A method has been devised for collecting hypophysial portal blood from the anaesthetised guinea pig in order to measure the release in vivo of the neurohypophysial peptides, oxytocin (OT), vasopressin (AVP), neurophysin (NP), and the glycopeptide (GP) found at the carboxyl terminus of the AVP precursor. These peptides were measured in samples of portal and peripheral venous plasma by specific radioimmunoassays. The concentration of OT and AVP was 50- to 100-fold higher in hypophysial portal blood than in peripheral blood, with more OT than AVP usually present. There were correspondingly large amounts of NP and GP also present in portal blood. In particular, GP levels paralleled AVP levels over a wide range of concentrations and in virtually equimolar proportions. These results provide the first in vivo evidence which shows that, as for the magnocellular neurohypophysial system, GP is synthesised, processed and released in equal amounts with AVP from their common precursor in the subpopulation of parvocellular AVP neurons which project from the paraventricular nucleus to the median eminence.

Animals↗

PubMed1988

Specificity of vasopressin binding to the posterior pituitary gland in the rat. An autoradiographic study.

Specific binding sites for vasopressin (AVP) were compared in the kidney and posterior pituitary gland from normal and homozygous Brattleboro rats using autoradiography with [3H]-AVP. The specificity of ligand binding was assessed by displacement with AVP analogues differing in specificity and potency. In the kidney, specific [3H]-AVP binding was found in the medulla, with much less in the cortex, in both normal and Brattleboro rats. Binding of [3H]-AVP was displaced most effectively by dDAVP and least by AVP-OH, in line with their relative antidiuretic potencies. In the pituitary gland, specific AVP binding was much higher in the posterior lobe than in the intermediate or anterior lobes. This posterior lobe AVP binding was greatly reduced in Brattleboro rats, even in animals given exogenous AVP to restore their water balance. It was unlikely that neurophysin binding was responsible since there was no correlation between [3H]-AVP displacement and neurophysin binding in a series of analogues slightly modified at the N or C terminus to affect selectively neurophysin or receptor binding. We suggest that specific AVP receptors may be present in the posterior pituitary gland, possibly on or in the AVP terminals themselves, associated with the normal synthesis, packaging and/or transport of AVP granules to the neural lobe.

Animals↗

PubMed1988

Comparison of adrenocorticotropin control in Brattleboro, Long-Evans, and Wistar rats. Measurement of corticotropin-releasing factor, arginine vasopressin, and oxytocin in hypophysial portal blood.

The purpose of this study was to compare the control of adrenocorticotropin (ACTH) and corticosterone secretion in homozygous Brattleboro rats with their syngeneic controls, Long-Evans rats, and with rats of the Wistar strain. Plasma concentrations of ACTH and corticosterone were measured by radioimmunoassay in trunk blood, and corticotropin-releasing factor 41 (CRF-41), arginine vasopressin (AVP), and oxytocin were assayed in hypophysial portal vessel blood. Portal plasma was extracted with methanol for CRF-41 determination, and four different antisera and several different high-performance liquid chromatography (HPLC) systems were used to investigate AVP release. The peripheral plasma concentrations of ACTH and corticosterone were significantly higher in Long-Evans and homozygous Brattleboro than in Wistar rats. This difference was due, at least in part, to an approximately twofold greater release of CRF-41 into hypophysial portal blood of the Long-Evans and Brattleboro compared with Wistar rats. There was no significant difference between the strains in the output of oxytocin into portal blood. While no AVP could be detected in the neural lobe of homozygous Brattleboro rats, a small amount of AVP-like immunoreactivity was detected in unextracted hypophysial portal blood from homozygous Brattleboro rats. However, this AVP-like immunoreactivity was clearly distinct from authentic AVP in several HPLC systems, had no antidiuretic activity, and on gel filtration had a relative molecular mass greater than 5 kD. In contrast, the AVP-like immunoreactivity in hypophysial portal blood from Long-Evans rats co-eluted with authentic AVP in all HPLC systems tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1988

Paradoxical growth-promoting effects induced by patterned infusions of somatostatin in female rats.

In previous studies with iv infusions of GH or its releasing factor (GRF), we showed that a pulsatile pattern of GH was more effective than continuous GH exposure in stimulating growth in the rat. Since GH release is profoundly affected by its inhibitory factor, somatostatin (SS), we were interested to know whether the effects of SS on GH secretion and growth were also dependent on its pattern of administration. SS infusions were given iv to conscious chronically cannulated female rats through programmable multichannel infusion pumps. Multiple blood samples were obtained with the use of an automated system of pumps, solenoid fluid valves, and a fraction collector, all controlled by a microcomputer. SS infusions (5, 25, or 50 micrograms/h) suppressed GH secretion and elicited a rapid, short-lived rebound release of GH after stopping the infusion. Sinusoidal SS infusions in female rats produced cyclic episodes of GH secretion, but a male type of regular 3-hourly secretory pulses of GH was best achieved by prolonged infusions in which the delivery of SS was interrupted for a short period every 3 h. This intermittent SS infusion pattern elicited a repetitive series of rebound bursts of GH secretion, which increased body weight gain and pituitary GH content. In contrast, continuous infusions of equivalent amounts of SS had no effect on body weight gain and reduced bone growth significantly. Thus the effects of SS on growth do depend on the pattern in which it is administered, and this peptide, which itself powerfully inhibits GH secretion, paradoxically stimulates weight gain in a normal animal when given in a manner that promotes a more pulsatile GH secretory pattern.

Animals↗

PubMed1988

Growth hormone-deficient dwarfism in the rat: a new mutation.

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)

Animals↗

PubMed1988

Growth hormone (GH) secretion in the conscious rat: negative feedback of GH on its own release.

The negative-feedback effects of GH on its own secretion were studied in conscious male and female rats bearing indwelling double-bore venous cannulae. Intravenous infusions of human GH (hGH; 20-60 micrograms/h) or somatostatin (SS; 10 micrograms/h) were given while frequent serial microsamples of blood were withdrawn using an automatic blood-sampling system. In both sexes, i.v. infusions of hGH for 6 h inhibited endogenous GH secretory pulses, with a slow onset of the inhibition. There was no rebound GH secretion immediately following the removal of the hGH infusion, but spontaneous GH secretion gradually returned to normal. Infusions of hGH did not inhibit the pituitary GH response to repeated GH-releasing factor (GRF) injections (1 microgram) given i.v. every 40 min to female rats. By contrast, infusions of SS, which also blocked spontaneous GH release, dramatically reduced the GH responses to serial GRF injections. When SS Infusions were stopped, the subsequent GRF-induced GH secretory responses were enhanced. These results show that GH can inhibit its own release when given by i.v. infusion to conscious male and female rats. Since GH responses to GRF are maintained during a GH infusion, the feedback effect of GH is unlikely to be exerted directly on the pituitary or by increasing SS release. Our results are consistent with the idea that GH feedback in the conscious rat involves an inhibition of GRF release.

Animals↗

PubMed1988

The rebound release of growth hormone (GH) following somatostatin infusion in rats involves hypothalamic GH-releasing factor release.

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.

Animals↗

PubMed1988

Growth promoting activity of IGF-I in the rat.

According to the original somatomedin hypothesis, GH promotes growth by generating 'somatomedins' or insulin-like growth factors (IGFs) in the liver. The advent of large amounts of IGF-I produced by recombinant DNA technology has now allowed testing of this hypothesis, by comparing the growth promoting activity of IGF-I and GH in three animal models of growth deficiency. When injected or infused subcutaneously, or infused intravenously, IGF-I is a weak growth promoter in the hypophysectomized rat compared with GH, even when infused in combination with small amounts of GH. Growth arrest in the diabetic rat was corrected by insulin infusion which also restored GH secretion. Insulin or IGF-I caused a large initial weight gain in diabetic rats, accompanied by a partial correction of food and water balance, even in the presence of persistent hyperglycaemia. A new mutant GH deficient dwarf rat grows in response to both GH and IGF-I infusions, but these agents elicit different patterns of organ growth. For the same overall body growth, GH was more effective in stimulating bone growth, whereas IGF-I stimulated renal and splenic growth. This new dwarf rat may prove useful for the study of the relative growth promoting effects of IGF-I and GH in more detail in future.

Animals↗

PubMed1987

Recombinant human insulin-like growth factor: testing the somatomedin hypothesis in hypophysectomized rats.

The in-vivo biological activity of recombinant methionyl insulin-like growth factor I (met-IGF-I) was demonstrated in hypophysectomized rats by following blood glucose after an i.v. bolus injection of met-IGF-I; a dose-dependent decrease in blood sugar was seen. Membrane transport was studied using the non-metabolizable amino acid alpha-aminoisobutyric acid; stimulation was obtained with the highest dose used (90 micrograms/rat). To test the original somatomedin hypothesis, growth studies were performed in hypophysectomized rats. Two or three doses of met-IGF-I were given with three different administration regimes (i.v. or s.c. infusion, or s.c. injections twice daily) for 6 or 8 days. Little growth-promoting activity was observed, with a significant effect on body weight gain obtained only when met-IGF-I was given continuously at the highest dose used (180 micrograms/day). No effect was seen on the in-vivo uptake of radioactive sulphate into cartilage. Epiphyseal cartilage width increased slightly at the highest dose of met-IGF-I, but only when the hormone was given by infusion. When 180 micrograms met-IGF-I/day were given by injections, a significant effect on longitudinal bone growth was obtained (90 micron above control). The levels of IGF in the serum were not measurably increased after s.c. administration of met-IGF-I, whereas after i.v. infusion, significantly raised levels were obtained at the higher dose rates (3.0 +/- 0.3 and 2.8 +/- 0.1 units/ml). Growth hormone was much more effective than met-IGF-I even at 50-fold lower doses. Priming the animals with 10 mu. bovine GH/day followed by combined infusions of GH and met-IGF-I did not reveal any potentiating effects of met-IGF-I in the presence of GH. We conclude that met-IGF-I is a relatively poor growth-promoting agent when given systemically, and that somatomedins are more likely to act as local growth factors rather than as circulating mediators of the growth-promoting effects of GH.

Animals↗

PubMed1987

Growth hormone secretory profiles in conscious female rats.

An automatic method for repetitive microsampling of blood from conscious animals was used to obtain detailed GH secretory profiles from normal female rats, which were compared with those in males and ovariectomized females. Female rats showed a highly variable GH secretory pattern, with sustained periods of low, almost continuous secretion, followed by very rapid bursts of high amplitude and short duration, occurring mostly at night. There was no clear relationship between the pattern of GH secretion and the phase of the oestrous cycle in rats continuously sampled over a 5-day period. In ovariectomized rats, the day:night difference was maintained, though the nocturnal GH surges were larger and of longer duration than in intact females. Male rats produced multicomponent GH bursts which continued unchanged throughout the day and night. This study shows for the first time that female rats switch to a rapid, highly pulsatile pattern of GH release at night, which can only be resolved by rapid blood sampling over extended periods in conscious undisturbed animals.

Animals↗