Inhibition by antiserum to rat growth hormone-releasing factor of growth hormone secretion induced by a met5-enkephalin analog, FK33-824, in rats

A Met5-enkephalin analog, FK33-824 (5, 10 and 20 micrograms/100 g body wt, iv) caused a dose-related increase in plasma growth hormone (GH) in urethane-anesthetized male rats. Pretreatment with cysteamine (30 mg/100 g body wt, sc), a depletor of hypothalamic somatostatin, increased the plasma GH response to FK33-824 (10 micrograms/100 g body wt, iv). Antiserum specific for rat GH-releasing factor (GRF) (0.5 ml/rat, iv) blunted GH release induced by FK33-824 (10 micrograms/100 g body wt, iv) in rats with or without cysteamine pretreatment. These results suggest that GH secretion induced by the opioid peptide is mediated, at least in part, by hypothalamic GRF in the rat.     

Effect of dopamine, bombesin and cysteamine hydrochloride on plasma growth hormone response to synthetic growth hormone-releasing factor in rats

In urethane anesthetized rats, an intracerebroventricular (icv) injection of 2 micrograms bombesin 5 min prior to the administration of synthetic human growth hormone-releasing factor (GRF) (1 microgram/kg, iv) inhibited plasma growth hormone (GH) response, while cysteamine hydrochloride (90 mg/kg, sc) administered 150 min beforehand depleted immunoreactive somatostatin content in the pituitary-stalk median eminence and consequently potentiated the response to GRF. Under the same experimental conditions, central injection of 1.89 micrograms (10(-8)M) dopamine hydrochloride or iv administration of L-DOPA (10 mg/kg) did not influence the subsequent plasma GH response to GRF. Results suggest indirectly that bombesin and cysteamine, but not dopamine, predominantly modulate somatostatin release from the hypothalamus.     

Growth hormone, thyrotropin and prolactin responses to simultaneous administration of human growth hormone-releasing factor and thyrotropin releasing hormone in the bovine

The effects of intravenous injection of synthetic human pancreatic growth hormone-releasing factor-44-NH2 (hpGRF-44) and synthetic thyrotropin releasing hormone (TRH), or hpGRF-44 in combination with TRH on growth hormone (GH), thyrotropin (TSH), and prolactin (PRL) release in dairy female calves (6- and 12-month-old) were studied. When 0.25 microgram of hpGRF-44 per kg of body weight (bw) was injected in combination with TRH (1.0 microgram per kg of bw), the mean plasma GH concentration of the 12-month-old calves rose to a maximum level of 191.5 ng/ml (P less than 0.001) at 15 min from the value of 6.8 ng/ml before injection at 0 min. The maximum level was 3.1 and 6.1 times as high as the peak values obtained after injection of hpGRF-44 (0.25 microgram per kg of bw) and TRH (1.0 microgram per kg of bw), respectively (P less than 0.001). The area under the GH response curve for the 12-month-old calves for 3 hr after injection of hpGRF-44 in combination with TRH was 2.5 times as large as the sum of the areas obtained by hpGRF-44 and TRH injections. In contrast, the mean plasma GH level was unchanged in saline injected calves. The magnitudes of the first and the second plasma GH responses in the 6-month-old calves to two consecutive injections of hpGRF-44 in combination with TRH at a 3-hr interval were very similar. The peak values of plasma GH in the calves after hpGRF-44 injection were 2-4 times as high as those after TRH injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of the frequency of subcutaneous insulin-like growth factor-1 administration on weight gain in growth hormone deficient mice.

To ascertain the frequency of subcutaneous IGF-1 administration necessary to promote growth we examined the weight gain of male homozygous lit/lit mice in response to either sc. IGF-1 or bovine GH administration. Lit/lit mice showed a dose dependent response to treatment with GH. Bovine GH induced a response in body weight gain within 3 days of the start of treatment. Following a single subcutaneous injection of IGF-1, plasma IGF-1 levels were elevated for 4-6 hours. Three treatment schedules for IGF-1 were used (once daily, twice daily and four times daily), each employing the same total daily dose of IGF-1 (30 micrograms). With IGF-1 treatment, a significant effect on body weight gain was obtained when administered four times daily. The growth rate with IGF-1 treatment 6 hourly was similar to that observed following treatment with bGH (10 micrograms sc daily). Twelve hourly IGF-1 administration only had a significant effect on body weight gain when weight was measured in the evening. Lit/lit mice treated once daily with 30 micrograms IGF-1 had no weight gain response and became severely hypoglycaemic. Frequent subcutaneous IGF-1 administration is one approach to growth enhancement in GH deficiency; higher doses administered less frequently do not promote growth and may cause hypoglycaemia.     

Growth hormone response to human pancreatic growth hormone releasing factor in cattle

The effects of a growth hormone releasing factor, human pancreatic growth hormone releasing factor-44 (hpGRF-44), on growth hormone (GH) secretion in calves, heifers and cows were studied. A single intravenous (iv) injection of 0.1, 0.25, 0.5 or 1.0 microgram of synthetic hpGRF-44 per kg of body weight (bw) in calves significantly elevated the circulating GH level within 2-5 min, while no increase in plasma GH was observed in saline injected control calves. The plasma GH level increased proportionally to the log dose of hpGRF-44, and reached a peak at 5-10 min (p less than 0.01). Subcutaneous injection of hpGRF-44 also elevated the plasma GH level, but the peak value at 15 min was 37% of that of iv injection (p less than 0.05). Intravenous injection of 0.25 microgram of hpGRF-44 per kg of bw to female calves, heifers, and cows significantly elevated mean the GH levels from 8.5, 2.3, and 1.6 ng/ml at 0 time to peak values of 97, 26, and 11.6 ng/ml, respectively (p less than 0.01). The plasma GH response and basal level in calves were significantly higher than those of heifers or cows (p less than 0.025). The plasma GH response to hpGRF-44 as well as the basal level decreased with advancing age. The plasma GH response to hpGRF-44 and basal GH in male calves were significantly greater than those in female calves (p less than 0.001). These results indicate that synthetic hpGRF-44 is a potent secretogogue for bovine GH, and suggest its usefulness in the assessment of GH secretion and reserve in cattle.     

Effects of highly potent octapeptide analogs of somatostatin on growth hormone, insulin and glucagon release

Biological activities of highly potent octapeptide analogs of somatostatin (SS), D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), were investigated in male rats. When analog RC-160 was administered to rats in which serum growth hormone (GH) levels were elevated by pentobarbital anesthesia, a dose-related inhibition of GH was obtained at dose range of 0.1 to 2.5 micrograms/kg. The time course of GH inhibition by RC-160, RC-121 and SS-14 was studied in rats treated with phenobarbital, morphine and chlorpromazine. Analogs RC-160 and RC-121 induced a prolonged inhibition of GH levels, in contrast to SS-14, whose effect was short-lived. The analogs suppressed the GH level for more than 2 hr, the peak inhibition being seen 30 to 60 min after the injection. The effects of analogs RC-160 and RC-121 on insulin secretion were observed in rats, in which insulin levels had been elevated by intravenous administration of glucose (500 mg/rat). Administration of RC-160 suppressed insulin secretion, dose-dependently, maximum but not complete inhibition being achieved at a dose of 100 micrograms/kg. In this model, RC-160 and RC-121, in doses of 30 micrograms/kg, induced a similar inhibition of insulin release as 200 micrograms/kg of SS-14, whose action of SS-14 was transient. The effect of analog RC-160 on glucagon release was studied in rats with glucagon levels elevated by hypoglycemia. RC-160 suppressed the secretion of glucagon, the inhibition being dose-dependent in the range of 0.1 to 2 micrograms/kg. Doses of 2 and 10 micrograms/kg of this analog completely suppressed the hypoglycemia-induced glucagon release. These results indicate that analogs RC-160 and RC-121 possess prolonged and enhanced biological activities, the former analog showing a high selectivity in inhibiting GH and glucagon release in vivo as compared with that of insulin secretion.     

Response of growth hormone release to human growth hormone-releasing factor and its analogs in the bovine

Responses of growth hormone (GH) release to synthetic human growth hormone-releasing factor (hGRF)-44-NH2 analogs were determined, and the GH-releasing potency based on dose per kg of body weight (bw) was compared with that of hGRF-44-NH2 in female dairy calves. Four- and 12-month-old calves were injected intravenously with 0.25 microgram of hGRF-44-NH2 or its analogs per kg of bw. Blood samples were collected before, and during 180 min after each injection, and plasma GH concentrations were measured by radioimmunoassay. Areas under the GH response curves for 180 min after injection of hGRF-44-NH2 and its analogs were used as an index of the GH-releasing potency of each peptide. The GH-releasing potency of hGRF(1-26)-NH2 was significantly lower than that of hGRF-44-NH2 (P less than 0.05). On the other hand, hGRF(1-29)-NH2 possessed similar potency to hGRF-44-NH2. [D-Tyr1]-hGRF-44-NH2 showed prolonged GH-releasing activity, though its potency was similar to that of hGRF-44-NH2. Also, [D-Ala2]-hGRF(1-29)-NH2 exhibited prolonged GH-releasing activity, and its potency was 2.5 (P less than 0.05) and twice (P less than 0.05) as great as that of hGRF-44-NH2 and hGRF(1-29)-NH2, respectively. These results demonstrate that the N-terminal 29 amino acid residues of hGRF possess the activity site required for full GH release in vivo, and [D-Ala2]-hGRF(1-29)-NH2 has longer and greater activity, on a dose basis, than hGRF-44-NH2 in the calves.     

Growth hormone responses to growth hormone-releasing hormone (1-29)-NH2 and a D-Ala2 analog in normal men

Synthetic analogs of growth hormone-releasing hormone, GHRH(1-29)-NH2 and D-Ala2 GHRH(1-29)-NH2 were administered as a bolus intravenous injection to five normal men in a dose range of 0.015 to 0.5 micrograms/kg body weight. Vehicle only was administered in a control study. Peak responses to GHRH analogs occurred at 15 or 30 min. An increase in the integrated plasma growth hormone (GH) response was observed at each dose. The dose-response curve of GHRH(1-29)-NH2 indicated that it has a similar molar potency to GHRH(1-40) and GHRH(1-44). The potency of D-Ala2 GHRH(1-29)-NH2 was approximately twice that of GHRH(1-29)-NH2. Neither analog affected blood levels of PRL, TSH, LH, FSH, ACTH, insulin, glucagon, glucose, cortisol, free thyroxine, and free triiodothyronine. No side effects were noted other than transient flushing with the highest dose administered. The findings demonstrate GHRH(1-29)-NH2 and its D-Ala2 analog are potent stimulators of GH release and have potential application in clinical medicine.     

The effect of cyproheptadine on plasma growth hormone (GH) and on somatostatin response to GH-releasing hormone in man

Cyproheptadine (CPH)--a putative serotonin antagonist--is known to inhibit growth hormone (GH) response to various pharmacological stimuli, as well as during sleep. To elucidate the possible site at which this drug takes effect, we examined plasma GH and somatostatin response to i.v. GHRH1-44 (1 microgram/kg body wt.) before and after CPH treatment in 10 healthy volunteers. The oral administration of CPH (8-12 mg daily for 5 days; total dose 56 mg) significantly curbed GH response to GHRH as expressed in peak plasma GH values (32.0 +/- 6.1 micrograms/l vs. 12.6 +/- 3.2 micrograms/l; P less than 0.01) and in integrated GH response area (2368 +/- 517 micrograms x l-1 x 2 h vs. 744 +/- 172 micrograms x l-1 x 2 h; P less than 0.01). Plasma somatostatin levels did not change in response to GHRH.     

Plasma growth hormone responses to repetitive administrations of growth hormone releasing factor in patients with pituitary dwarfism

Plasma growth hormone (GH) responses to the repetitive administrations of synthetic human pancreatic growth hormone releasing factor (hpGRF-44) were studied in 15 patients with GH deficiency (11 diagnosed as idiopathic and 4 diagnosed as secondary to hypothalamo-pituitary tumor). hpGRF-44 was administered by single iv bolus (2 micrograms/kg), repetitive im (100 micrograms, twice a day), and/or repetitive iv infusion (2.5 micrograms/min for 90 min, once a day) for three to six consecutive days. Three of the eleven idiopathic GH deficient patients had plasma GH responses to both single iv bolus injection and repetitive administrations by im, or iv infusion of hpGRF. In four of the remaining eight, who had not had peak plasma GH levels above 5 ng/ml to a single iv bolus of the peptide, repetitive administrations of hpGRF-44 by im injection and/or iv infusion induced GH responses to the peptide. In the four patients with secondary GH deficiency, three had plasma GH response to hpGRF administration but one patient, who had indications of pituitary disorder, did not show any plasma GH response to either single iv injection or repetitive administrations of hpGRF-44. These data show that repetitive administrations of hpGRF-44 can induce plasma GH responses in some GH deficient patients who do not respond to a single iv bolus of the peptide.     

The inter- and intra-subject variabilities of plasma GH response to human growth hormone-releasing hormone (1-44) NH2 in men

The effects of intravenously given human growth hormone-releasing hormone (1-44) NH2 (hGRH-44) on growth hormone (GH) secretion were studied in normal men. A wide variability of intersubject GH response to hGRH-44 was observed. The peak plasma GH levels in response to 50, 100 and 200 micrograms hGRH-44 in 7 normal men were 9.1 +/- 3.2 ng/ml (Mean + SEM), 19.3 +/- 3.3 ng/ml and 22.4 +/- 4.0 ng/ml, respectively. Both the mean peak values for plasma GH response to 100 and 200 micrograms were significantly greater than that for 50 micrograms hGRH-44 injection (p less than 0.01), although there was no significant difference of the mean peak plasma GH values and mean concentrations at each time point, except for those at 120 min, when 100 or 200 micrograms hGRH-44 was administered. A significant difference in the mean amount of plasma GH secreted in response to hGRH-44 was observed only between 50 and 200 micrograms hGRH-44 injection (p less than 0.01). Furthermore, a dose-related plasma GH increase in response to hGRH-44 was not always observed in each subject. In contrast to the wide intersubject variability, the difference among responses of plasma GH to 100 micrograms or 200 micrograms of hGRH-44 given at multiple times separated by intervals of at least 1 week in each individual was relatively small.(ABSTRACT TRUNCATED AT 400 WORDS)     

Modulation of luteinizing hormone(LH) release by clonidine and opioid peptides in castrated male rats

The effect of clonidine, a central alpha-adrenergic agonist, on the suppression of LH release induced by beta-endorphin or FK33-824, an endogenous opioid peptide or its synthetic analog, was investigated in castrated male rats, with or without pretreatment with reserpine. Pulsatile LH secretion was inhibited by intravenous injection of FK33-824 (400 micrograms/kg), or intraventricular injection of beta-endorphin (5 micrograms). Without pretreatment with reserpine, intraperitoneal administration of clonidine (1 mg/kg) failed to reverse the inhibition of LH release induced by these peptides. However, with pretreatment with reserpine (10 mg/kg), clonidine abolished the inhibitory effect on LH secretion induced by these peptides in castrated male rats. These data indicate that, unlike the results in ovariectomized, steroid-primed rats, pretreatment with reserpine allows the alpha-adrenergic system to act more peripherally than the opioid neuronal system in a neuronal network-regulating LH release in castrated male rats.     

Evaluation of the biological potency of new agmatine analogs of growth hormone-releasing hormone in the bovine.

Four new growth hormone-releasing hormone (GHRH) analogs with C-terminal agmatine were compared with the parent human GHRH(1-29)NH2 fragment to assess their abilities to increase serum concentrations of growth hormone (GH) in the bovine. The four analogs were: [D-Ala2, Nle27] GHRH(1-28)Agm (JG-73); [desNH2-Tyr1, Ala15, Nle27] GHRH(1-28)Agm (MZ-2-51); [desNH2-Tyr1, Ala15, D-Lys21, Nle27] GHRH(1-28)Agm (MZ-2-75); and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GHRH(1-28)Agm (MZ-2-87). The special characteristic of all four GHRH analogs is that arginine was replaced by agmatine (Agm) in Position 29. Five pregnant Holstein cows received these peptides subcutaneously at the following doses: 0.0156, 0.0625, 0.25, 1, and 4 micrograms/kg body wt. Each cow received each analog-dose combination according to a 5 x 5 Greco-Latin square design repeated for the 5-week treatment. Each cow also received saline vehicle only at the end of the 5-week treatment. Blood samples were collected from 30 min before until 360 min after treatment injection. Total area under the GH response curves for the 6-hr sampling period for each dose of each GHRH analog was compared. There was a linear dose-dependent GH release in response to hGHRH(1-29)NH2 and its four GHRH(1-28)Agm analogs. At the dose of 0.25 micrograms/kg, two GHRH analogs, JG-73 and MZ-2-75, stimulated greater GH release than hGHRH(1-29)NH2 (P less than 0.05). No differences were seen at the two lowest doses, 0.0625 and 0.156 micrograms/kg. When both total area under the GH response curves and GH peak amplitudes for each treatment were averaged for all doses, JG-73 and MZ-2-75 stimulated greater GH release than hGHRH(1-29)NH2 (P less than 0.05). In summary, three GHRH(1-28)Agm analogs, JG-73, MZ-2-75, and MZ-2-51, were found to be 11.8, 11.3, and 6.5 times more potent, respectively, on a weight basis, than hGHRH(1-29)NH2 in stimulating the release of GH in cows.     

Robust growth hormone (GH) secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and GH-releasing hormone (GHRH)

Aging is associated with a blunted growth hormone (GH) secretory response to GH-releasing hormone (GHRH), in vivo. The objective of the present study was to assess the effects of aging on the GH secretory response to GH-releasing hexapeptide (GHRP-6), a synthetic GH secretagogue. GHRP-6 (30 micrograms/kg) was administered alone or in combination with GHRH (2 micrograms/kg) to anesthetized female Fischer 344 rats, 3 or 19 months of age. The peptides were co-administered to determine the effect of aging upon the potentiating effect of GHRP-6 on GHRH activity. The increase in plasma GH as a function of time following administration of GHRP-6 was lower (p less than 0.001) in old rats than in young rats; whereas the increase in plasma GH secretion as a function of time following co-administration of GHRP-6 and GHRH was higher (p less than 0.001) in old rats than in young rats (mean Cmax = 8539 +/- 790.6 micrograms/l vs. 2970 +/- 866 micrograms/l, respectively; p less than 0.01). Since pituitary GH concentrations in old rats were lower than in young rats (257.0 +/- 59.8 micrograms/mg wet wt. vs. 639.7 +/- 149.2 micrograms/mg wet wt., respectively; p less than 0.03), the results suggested that GH functional reserve in old female rats was not linked to pituitary GH concentration. The differential responses of old rats to individually administered and co-administered GHRP-6 are important because they demonstrate that robust and immediate GH secretion can occur in old rats that are appropriately stimulated. The data further suggest that the cellular processes subserving GH secretion are intact in old rats, and that age-related decrements in GH secretion result from inadequate stimulation, rather than to maladaptive changes in the mechanism of GH release.     

Chronic growth hormone administration does not suppress endogenous growth hormone secretion in patients with neurosecretory growth hormone dysfunction.

Short children who respond normally to growth hormone (GH) stimulation, but have a subnormal spontaneous secretion of GH (neurosecretory GH dysfunction, NSD) are treated with exogenous GH which might suppress their endogenous GH secretion. The effect of chronic administration of GH (8-24 months) on plasma GH responses to GHRH, clonidine and spontaneous GH secretion were studied in 17 NSD patients. The diagnosis of NSD was based on a normal GH response to clonidine (greater than 10 micrograms/l) and an integrated concentration of (IC-GH) GH less than 3.2 micrograms/l. The GH dose used in this study was 0.25 IU/kg three times a week in 10 patients and 0.05 IU/kg daily in 7 patients. Insulin-like growth factor I levels (nmol) increased significantly on therapy from 9.3 +/- 3.8 to 24.4 +/- 22.4 (p less than 0.001). The GH response (microgram/l) to GHRH was 20.4 +/- 5.5 before treatment and 22.4 +/- 6.2 on GH. Peak GH after clonidine was 22.4 +/- 8.9 and 22.8 +/- 8.1, respectively. There was no significant decrease in the number of GH spontaneous peaks (1.8 +/- 0.7 vs. 2.0 +/- 0.7, respectively) or in the area under the curve. A subcutaneous GH bolus of 0.25 IU/kg in 4 patients resulted in a GH peak of 55-82 micrograms/l at 3-5 h and a gradual return to basal levels at 15-20 h after GH administration. The first spontaneous GH peak appeared 26-28 h after GH injection, peak amplitude was 10-15 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma GH and somatomedin C responses to single and repeated administrations of human growth hormone releasing factor (hGRF)

Plasma growth hormone (GH) and somatomedin C responses to single and repeated administrations of synthetic human growth hormone releasing factor (hGRF-44) were studied in 29 patients with GH deficiency. hGRF-44 administered by single iv bolus (10 micrograms/kg), repeated iv boluses (50 or 100 micrograms, once a day), repeated iv infusions (2.5 micrograms/min for 90 min, once a day), and/or repeated im injections (100 micrograms, twice a day) for three to six consecutive days. Ten of 16 patients had plasma GH responses to a single iv bolus injection, i.e., their plasma GH increased above 5 ng/ml or twice the basal level. However none of them showed a plasma somatomedin C increase. To repeated iv bolus injections and repeated iv infusions of hGRF-44, 7 of 17 patients showed plasma GH responses, however in none of 7 patients did somatomedin C increase. Plasma somatomedin C did not increase after repeated im administrations of hGRF-44 for 5 days. Plasma somatomedin C increase was observed in two patients, from 0.32 to 0.54 U/ml and from 0.16 to 0.46 U/ml, in response to repeated iv boluses and repeated iv infusions, respectively. These results suggest that hGRF-44 stimulates plasma GH secretion in some patients with GH deficiency, however the increases are not enough to stimulate somatomedin generation.     

Evaluation of in vivo [corrected] biological activity of new agmatine analogs of growth hormone-releasing hormone (GH-RH)

The effects of agmatine analogs of growth hormone releasing hormone (GH-RH) were compared to GH-RH(1-29)-NH2 after intravenous (iv) and subcutaneous (sc) administration to pentobarbital-anesthetized male rats. After the iv injection, the analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-51); [desNH2-Tyr1,D-Lys12,Ala15,Nle27] GH-RH(1-28)Agm (MZ-2-57); [desNH2-Tyr1,Ala15,D-Lys21,Nle27] GH-RH(1-28)Agm (MZ-2-75) and [desNH2-Tyr1, D-Lys12,21, Ala15, Nle27] GH-RH(1-28)Agm (MZ-2-87) showed a potency equivalent to 4.4, 1.9, 1.07 and 1.03 times that of GH-RH (1-29)-NH2, respectively, at 5 min and 5.6, 1.8, 1.9 and 1.8 times higher, respectively, at 15 min. After sc administration, analogs MZ-2-51, MZ-2-57 and MZ-2-75 showed to be 34.3, 14.3 and 10.5 times more potent than the parent hormone at 15 min and 179.1, 88.9 and 45.0 times more active, respectively, at 30 min. In addition, MZ-2-51 had prolonged GH-releasing activity as compared to the standard. We also compared the activity of MZ-2-51 and MZ-2-57 with their homologous L-Arg and D-Arg analogs [desNH2-Tyr1,Ala15,Nle27] GH-RH(1-29)-NH2 (MZ-2-117), [des-NH2Tyr1,D-Lys12, Ala15, Nle27] GH-RH(1-29)NH2 (MZ-2-123) and [desNH2-Tyr1,D-Lys12,Ala15, Nle27,D-Arg29] GH-RH(1-29)NH2 (MZ-2-135) after intramuscular (im) injection. MZ-2-51 induced a somewhat greater GH release than MZ-2-117 at 15 min, both responses being larger than the controls (p less than 0.01) at 15 and 30 min. MZ-2-57, MZ-2-123 and MZ-2-135 given i.m. were able to stimulate GH release only at 15 minutes (p less than 0.05). Animals injected i.m. with MZ-2-51, but not with MZ-2-117, showed GH levels significantly higher than the control group (p less than 0.05) at 60 min. GH-RH(1-29)NH2 had low activity intramuscularly when tested at a dose of 2.5 micrograms. No toxic effects were observed after the iv administration of 1 mg/kg of Agm GH-RH analogs. These results indicate that our Agm analogs are active iv, sc and im and that the substitutions made in these compounds produce increased and prolonged GH releasing activity. These analogs, especially MZ-2-51, should be useful for clinical and veterinary purposes.     

Central somatostatinergic regulation of growth hormone secretion in dwarf chickens.

1. Basal circulating growth hormone (GH) concentrations in sex-linked-dwarf (SLD) chickens were unaffected by the intracerebroventricular (icv) injection of 10, 50 or 100 micrograms somatostatin (SRIF). 2. The GH response to systemic thyrotropin-releasing hormone (TRH; 10 micrograms/kg, iv) was, however, 'paradoxically' enhanced 20 min after icv SRIF administration. 3. A lower dose (1.0 micrograms) of SRIF had no effect on basal or TRH-induced GH release. 4. High-titre SRIF antisera (4 microliters) also had no acute effect on basal plasma GH concentrations, but augmented the GH response to TRH challenge. 5. SRIF would appear to act at central sites to modulate stimulated GH secretion in SLD chickens.     

Effect of long-term GHRH and somatostatin administration on GH release and body weight in prepubertal female rats

In order to find a chronic GHRH administration capable of stimulating growth rate without depleting pituitary GH content, prepubertal female rats were subcutaneously (sc) treated with GHRH (1-29)-NH2 and somatostatin (SS). In experiment 1, the rats received sc injections of GHRH and cyclic natural SS for 19 days. In the second study, female rats were continuously treated during 21 days with GHRH, using a slow release pellet, alone or combined with one daily injection of long acting SS (octreotide). In experiment 1, body weight was significantly increased when GHRH was administered at the highest daily dosage (1200 microg/day), accompanied by an slight increment in pituitary GH content. Hypothalamic SS concentrations decreased when GHRH or SS were administered alone whereas the combined treatment with both peptides did not modify this parameter, which suggests the existence of a balance between the chronic actions of both peptides on hypothalamus. In experiment 2, the continuous infusion of GHRH increased plasma GH levels and tended to enhance pituitary GH content. Nevertheless, GHRH effect was not effective enough to increase body weight. By adding one daily injection of SS both GHRH effects on the pituitary gland were abolished. Our study indicates that female rats retain responsiveness to chronic GHRH and SS treatments at both pituitary and hypothalamic levels.     

Plasma growth hormone, insulin-like growth factor-I, and milk production responses to exogenous human growth hormone-releasing factor analogs in dairy cows

Responses of plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I), and milk production to subcutaneous (sc) injection(s) of two synthetic human growth hormone-releasing factor (hGRF) analogs were studied in dairy cows. Two mg of each hGRF analog dissolved in 5 ml saline per cow were injected into the shoulder area of each experimental animal, and jugular venous blood samples were collected via an indwelling catheter or by venipuncture. Plasma GH and IGF-I concentrations were measured by radioimmunoassay methods. In dry cows, the mean concentration of plasma GH after a single sc injection of hGRF analogs rose to 22.0-28.3 ng/ml at about 5 h from 1.4-1.7 ng/ml at 0 h (just before injection), and returned to the level before injection after 10-12 h. On the other hand, the plasma IGF-I began to increase after a lag of 4-6 h following a single injection of hGRF analogs, and reached maximum values of 71.1-89.4 ng/ml at 20 h from 43.7-46.4 ng/ml at 0 h. The IGF-I concentration at 24 h after a single injection of hGRF analogs was still higher than the value for the dry cows given saline. In lactating cows, the plasma concentration of GH at 2 h after daily sc injections of hGRF analogs during 14 consecutive days (an injection period) was higher than those for the lactating cows which received saline. Also, during the injection period, the concentration of IGF-I was higher in the lactating cows which received hGRF analog injections than in the cows which received saline injections. During the last 7 days of the injection period, the administration of hGRF analogs increased the mean milk yield by 11-19% in comparison with those for the saline injected cows. A positive correlation was observed between the mean plasma IGF-I concentration and the mean milk yield in the lactating cows treated with hGRF analogs throughout the injection and a postinjection (11 consecutive days after cessation of hGRF analog injection) periods. The results demonstrate that a single sc injection of hGRF analogs stimulates both GH release and the circulating level of IGF-I in dry cows, and that daily sc injections of hGRF analogs over 14 days enhance milk production, and plasma GH and IGF-I levels in lactating cows.