Somatocrinin,growth hormone releasing factor,stimulates secretion of growth hormone in anesthetized rats

The synthetic replicate of a 44 amino acid peptide isolated from a human pancreatic tumor which had caused acromegaly possesses high specific activity to release growth hormone (GH) in anesthetized male rats. The GH secretion induced by this peptide is dose-dependent from 50 ng to 1 μg, with plasma GH concentrations increasing more than 10-fold within 5 min of iv administration at the higher doses. Two enzymatic degradation products of the 44 residue peptide were also isolated and consist of the first 37 and 40 amino acids. All three peptides appear to possess similar potency, on a molar basis, $\text{in}\text{vivo}$, contrary to $\text{in}\text{vitro}$ results. The specificity of these peptides on GH release was shown by their failure to alter plasma concentrations of prolactin (PRL), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and corticosterone. Based on these $\text{in}\text{vivo}$ results, the three peptides with serve as powerful tools with which to investigate the mechanisms of GH secretion.     

Effects of substance P and neurotensin on growth hormone and thyrotropin release in vivo and in vitro

Conscious ovariectomized (OVX) rats bearing a cannula implanted in the third ventricle were injected with 2 μl of 0.9% NaCl containing varying doses of substance P (SP) or neurotensin (NT) and plasma GH and TSH levels were measured by RIA in jugular blood samples drawn through an indwelling silastic catheter. Control injections of physiologic saline iv or into the third ventricle did not modify plasma hormone levels. Intraventricular injection of SP or NT at doses of either 0.5 or 2 μg elevated plasma GH concentrations within 5 min and they remained elevated for 60 min. Third ventricular injection of similar doses of SP or NT had no effect on plasma TSH. An intermediate dose of 1 μg of SP or NT given iv had no effect on plasma GH but NT elevated plasma TSH. Incubation of hemipituitaries from OVX rats with varying doses of SP or NT did not alter GH release into the medium but TSH release was enhanced with NT at doses of 100 or more ng/ml of medium. It is suggested that SP acts centrally to stimulate growth hormone-releasing factor (GRF) or to inhibit somatostatin release and thereby enhance GH release and that NT acts directly on the pituitary to stimulate TSH release.     

Effects of the synthesized growth hormone releasing peptide,KP-102, on growth hormone release in sodium glutamate monohydrate-treated low growth rats

KP-102 (D-Ala-D-β-Nal-Ala-Trp-D-Phe-Lys-NH2), a new second generation hexapeptide, has a potent growth hormone (GH)-releasing action in vivo and in vitro. Here, we evaluated the GH-releasing action of KP-102 under pentobarbital (PB) anesthesia in neonatally sodium-glutamate-monohydrate-treated low growth (NMSG- LG) rats. The plasma GH level in NMSG-LG rats after i.v. administration of KP- 102 at 100 μg/kg was 1/6.7 (95% CL. 1/14.7–1/3.0) of that in normal rats given the same dose (p < 0.01). However, the increase was significant compared with that in normal rats after saline administration (p < 0.0l). The plasma GH releasing action of KP-102 at 100 μg/kg i.v. in rats with lesions in the bilateral hypothalamic arcuate nuclei (ARC), was about 1/6.3 (95% C.L. 1/12.4–1/3.2) of that in normal rats under PB anesthesia (p < 0.01). When KP-102 was injected into the ARC at doses of 0.0002, 0.02 and 2 μg/rat, GH release was dose-related (p < 0.01) under PB anesthesia. KP-102 at 2 μg i.c.v. also increased the plasma GH levels (p < 0.01) to about 1/8.3 (95% C.L. 1/22.7–1/3.1) of that by systematic administration, at the same potency as the ARC injection (1/13.7 and 95% C.L. 1/37.2–1/5.0). These findings suggest that KP-102 potently stimulates the GH release by a direct or indirect antagonism of somatostatin (SRIF) and growth hormone releasing hormone (GHRH) release in the hypothalamus and by a direct action on the pituitary. Furthermore, the GH-releasing action of KP-102 was similar and additive upon both regions in vivo at the maximum effective dose. Moreover, since the GH-release in response to KP-102 administration differed between NMSG-LG and normal rats, and since KP-102 increased the GH release even in NMSG-LG rats, it should be evaluated in the hypophysial GH secretion tests, and may be used to treat the hypophysial GH secretion insufficiency.     

Pituitary response to growth hormone-releasing factor in rats with functional or anatomical lesions of the central nervous system that inhibit endogenous growth hormone secretion

The pituitary growth hormone (GH) response to the growth hormone-releasing factor, hpGRF-44, was evaluated in male rats with various lesions of the central nervous system. These included an electrical lesion of the ventromedial hypothalamus, a chemical lesion of the arcuate nucleus induced by neonatal treatment with monosodium glutamate, a functional lesion of catecholamine synthesis with alpha-methyl-p-tyrosine or a functional lesion of catecholamine storage with reserpine. The first three lesions appear to partially inhibit normal somatostatin secretion since in every instance hpGRF-44 administration induced a significant increase in plasma GH concentrations. In contrast, reserpine blocked the GH response to hpGRF-44, presumably by stimulating somatostatin secretion. The pituitary GH response to hpGRF-44 in the above described models was enhanced by pretreatment of the rats with antibodies against somatostatin. The pituitary GH response to repeated injections of hpGRF-44 was also evaluated in rats with an anatomical lesion of the arcuate nucleus or a functional lesion of catecholamine synthesis. The maximum GH response did not vary over time to the repeated injections of hpGRF-44 in rats with lesions of the arcuate nucleus; however, interruption of catecholamine synthesis resulted in a significant decrease in the GH response to hpGRF-44 over time.     

Growth hormone and somatostatin interaction in the ulcerogenic effect of cysteamine in female rats

It is known that cysteamine's ulcerogenic effect depends, among others, on a depletion of somatostatin (SRIH). Since growth hormone (GH) affects the release of hypothalamic SRIH, we have studied the influence of GH and the GH-SRIH interaction on the severity of gastric mucosa lesions induced by cysteamine. Female rats of the Sprague-Dawley strain were pretreated with GH (1 mg/kg) and subjected to cysteamine-induced gastric lesions. We found that these animals showed an increased mortality and severity of gastric lesions. Pretreatment with SRIH (25 or 50 μg/kg) was followed by a decrease in mortality and of incidence and severity of gastric mucosa lesions as compared to those found in control animals pretreated with saline. The dose of 5μg/kg was ineffective in this respect. The combined administration of GH and SRIH revealed that cysteamine ulcerogenic action remained unchanged. It is possible that high levels of plasma GH, as induced by exogenous GH administration, may decrease the release of gastro-intestinal SRIH and this in turn may potentiate the ulcerogenic activity of cysteamine.     

Lack of growth hormone-releasing activity of (pyro)Glu-Ser-Gly-NH2

Youdaev $\text{et al.}$ (1) reported that (pyro)Glu-Ser-Gly-NH₂ isolated from bovine hypothalami or made synthetically stimulates the release of growth hormone (GH). Therefore, we synthesized the tripeptide and tested it in several $\text{in vivo}$ and $\text{in vitro}$ assay systems for GH releasing activity. Our results demonstrate that (pyro)Glu-Ser-Gly-NH₂ does not stimulate the release of immunoreactive GH from rat pituitaries $\text{in vitro}$ in doses of 0.1–1000 nanog/ml. Similarly, (pyro)Glu-Ser-Gly-NH₂, injected intravenously into rats in doses of 1μg and 10μg/rat or infused into a hypophysial portal vessel in doses of 0.01 μg and 0.1 μg/rat did not increase serum GH levels as measured by radioimmunoassay. When this tripeptide was injected intravenously in doses of 500 μg into sheep it did not raise plasma GH levels. These results demonstrate that under the conditions of this investigation (pyro)Glu-Ser-Gly-NH₂ does not display any GH-releasing activity.     

Single exposure to testosterone in adulthood rapidly induces regularity in the growth hormone release process

The neonatal gonadal steroid milieu is known to be important in imprinting the striking sexual dimorphism of growth hormone (GH) secretion; however, the influence of the sex steroids on GH control in adult life and their mechanism/site of action are largely unknown. In the present study, we tested the hypothesis that testosterone (T) subserves the gender-specific regularity of the GH release process in adulthood. The approximate entropy statistic (ApEn) was used to quantify the degree of regularity of GH release patterns over time. Eighteen hours after a single subcutaneous injection of 1 mg T, both sham-operated and ovariectomized (OVX) female adult rats displayed plasma GH profiles that were strikingly similar to the regular male-like ultradian rhythm of GH secretion. The highest ApEn values, denoting greater disorderliness of GH secretion, were observed in the ovary-intact group, and T injection significantly (P < 0.001) reduced this irregularity whether or not the ovaries were present. Serial intravenous injections of GH-releasing hormone (GHRH) caused a similar increase in plasma GH levels in sham-operated females independently of time of administration. In contrast, female rats administered T exhibited a male-like intermittent pattern of GH responsiveness to GHRH, the latter known to be due to the cyclic release of endogenous somatostatin. These results demonstrate that acute exposure to T during adult life can rapidly and profoundly "masculinize" GH pulse-generating circuits in the female rat. Our findings suggest that the enhanced orderliness characteristic of the GH release process in males, compared with females, is regulated by T. We postulate that this T-induced regularity is mediated at the level of the hypothalamus by inducing regularity in somatostatin secretion, which in turn governs overall GH periodicity.     

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.     

Biosynthesis of delta-aminolevulinic acid in the unicellular rhodophyte, cyanidium caldarium.

Intravenous injection of sheep antiserum to somatostatin in the rat not only increases basal plasma TSH levels but also potentiates TSH response following exposure to cold (5° C). Plasma levels of GH rise 2–3 fold during the first 3 h after injection of the antiserum, with a progressive decrease of the effect up to 10 h. Rhythmical change of serum GH levels during a 10-hour period of observation is not altered after antiserum injection. These data indicate that somatostatin plays a physiological role in the control of both TSH and GH secretion and suggest the involvement of GH-releasing hormone, in addition to somatostatin, in the GH release mechanism.     

Somatostatin inhibits prolactin secretion in the estradiol primed male rat

Somatostatin inhibits not only growth hormone secretion, but also the secretion of several other hormones. The role of somatostatin in prolactin (PRL) secretion has not been clearly demonstrated. The present study was undertaken to examine the effects of somatostatin on rat PRL secretion in several different circumstances where the circulating PRL level is elevated: (1) the estradiol primed intact male rat, (2) normal and (3) estradiol primed rats pretreated with pimozide, (4) normal and (5) estradiol primed hypophysectomized male rats with adenohypophyses grafted under the kidney capsule (HAG rat). Blood samples (70 microL) were taken every 2 min via an indwelling atrial cannula from conscious, unrestrained animals. In the estradiol primed intact rats, a bolus injection of somatostatin (10, 100, and 1000 micrograms/kg) lowered PRL levels in a dose-dependent manner. When the PRL concentration was elevated by the administration of pimozide (3 mg/kg), a dopaminergic receptor blocking agent, somatostatin was ineffective in decreasing plasma PRL concentration but the PRL concentration was lowered by somatostatin when the rat had been primed with estradiol. Somatostatin had no effect on the normal HAG rats, but lowered the plasma PRL concentration in the estradiol primed HAG rats. Since somatostatin inhibits PRL secretion only in the estradiol primed rats, it is suggested that estradiol priming creates a new environment, presumably via new or altered receptors, which can be inhibited by somatostatin.     

Effects of passive immunization of growth hormone-releasing hormone and somatostatin on growth hormone secretion under conditions of high somatostatin tone.

Pulsatile GH secretion decreases during food-deprivation in the rat. It has been hypothesized that this decrease is due to elevated hypothalamic somatostatin secretion. This is based on the observation that GH increases in food-deprived rats following removal of endogenous somatostatin using passive immunization techniques. Cognizant of the important stimulatory effects of growth hormone-releasing hormone (GHRH) on GH secretion, we sought to determine if this neuropeptide plays any role in mediating GH secretion in food-deprived rats. Male rats were prepared with indwelling venous catheters using sodium pentobarbital anesthesia seven days prior to experimentation. Animals were food-deprived for 72 h, after which control blood samples were drawn from -60 to 0 min. One group was then treated with normal rabbit serum (NRS), while a second group was treated with GHRH antiserum (GHRHab). At 55 min all animals received somatostatin antiserum (SSab). No animal exhibited any spontaneous GH peak during the one hour control period or in the subsequent one hour period following the administration of GHRHab or NRS. Absence of GH pulsatility during food-deprivation, coupled with no decrease in GH levels in food-deprived rats treated with GHRHab suggest that diminished GHRH pulsatility is likely during food-deprivation. Subsequent treatment of these animals with SSab resulted in an identical 2.5 fold increase in GH concentrations. This result suggests that GHRH is not involved in the GH rebound following somatostatin withdrawal in food-deprived rats.     

Oral activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in rats, dogs and monkeys

The purpose of this study was to evaluate the growth hormone (GH) releasing activity of orally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in rats, dogs and monkeys. Rats were administered GHRP-6 orally by gavage or parenterally through femoral artery catheters. Blood was collected before and after GHRP-6 administration for estimation of plasma GH and comparison of GH changes resulting from enteral and parenteral administration of the peptide. GHRP-6 was administered to dogs intravenously (i.v.) through cephalic vein catheters, intragastrically (i.g.) through esophagostomy tubes or intraduodenally (i.d.) through vascular access ports, and blood was collected before and after peptide administration for estimation of plasma GH. Cynomolgus monkeys were administered GHRP-6 i.g., and blood was collected from abdominal aorta for estimation of changes in plasma GH. Enteral activity of GHRP-6 was observed in all 3 species tested. In rats, ED50's for enteral and parenteral administration of GHRP-6 were 4 mg/kg and 28 micrograms/kg, respectively. Thus in rats, enterally administered GHRP-6 was 0.7% as bioactive as the parenterally administered peptide. In dogs GHRP-6 was slightly less potent than in rats, with ED50's for i.g. and i.v. administration approximately 15 mg/kg and 125 micrograms/kg, respectively. However, enteral potency of GHRP-6 in dogs was 0.8% of parenteral potency, and thus, comparable to that in rats. Additionally, comparison of plasma GH levels following i.g. vs i.d. administration in dogs suggested greater activity by the i.d. route. Monkeys were the species most sensitive to enterally administered GHRP-6, with plasma GH increased in those receiving i.g. doses as low as 0.3 mg/kg and an ED50 of 0.75 mg/kg compared to 4 and 15 mg/kg in rats and dogs, respectively. The results of this study demonstrate that GHRP-6 releases GH when administered directly into the gastrointestinal tract. Although enteral activity is approximately 1% of parenteral activity, GHRP-6 is potent, especially in primates which require relatively low doses to provoke GH release. These data suggest that orally active GHRP-6 may provide a practical therapeutic alternative to parenterally administered peptides such as GHRH, especially if enteral activity is enhanced with appropriate formulation.     

Somatostatin mediates the effect of growth hormone surges on splanchnic biogenic amines

Experiments were conducted in trained, conscious dogs fitted with an indwelling portal catheter. Radioenzymatic methods were employed for the quantitative measurement of plasma-free serotonin and catecholamines. An injection of ovine growth hormone (GH, 100 micrograms/kg) or an equimolar amount of somatostatin (somatotropin release inhibitory factor, SRIF, 7.5 micrograms/kg) into a saphenous vein led, within the first 15 min, to a transient but significant increase in plasma serotonin and a decrease in the concentrations of dopamine, norepinephrine, and epinephrine. The changes were frequently in excess of 40% of baseline values, and were found only in the portal and not in the peripheral circulation. When the animals were pretreated with an antiserum specifically directed against SRIF, GH surges no longer caused alterations in the portal levels of biogenic amines. Thus, the effects of spike concentrations of GH on plasma serotonin and catecholamines are apparently mediated by SRIF, a novel and unexpected function for a hormone that is known as an inhibitor of GH secretion.     

Effects of intraventricular injection of gastrin on release of LH,prolactin, TSH and GH in conscious ovariectomized rats

Conscious ovariectomized (OVX) rats bearing a cannula implanted in the 3rd ventricle were injected with 2 μl of 0.9% NaCl containing varying doses of synthetic gastrin and plasma gonadotropin, GH and TSH levels were measured by RIA in jugular blood samples drawn through an indwelling silastic catheter. Control injections of saline iv or into the 3rd ventricle did not modify plasma hormone levels. Intraventricular injection of 1 or 5 μg gastrin produced significant suppression of plasma LH and prolactin (Prl) levels within 5 min of injection. Injection of 1 μg gastrin had no effect on plasma GH, but increasing the dose to 5 μg induced a progressive elevation, which reached peak levels at 60 min. By contrast, TSH levels were lowered by both doses of gastrin within 5 min of injection and the lowering persisted for 60 min. Intravenous injection of gastrin had no effect on plasma gonadotropin, GH and TSH, but induced an elevation in Prl levels. $\text{In}$$\text{vitro}$ incubation of hemipituitaries with gastrin failed to modify gonadotropin, GH or Prl but slightly inhibited TSH release at the highest dose of 5 μg gastrin. The results indicate that synthetic gastrin can alter pituitary hormone release in unrestrained OVX rats and implicate a hypothalamic site of action for the peptide to alter release of a gonadotropin, Prl and GH. Its effect on TSH release may be mediated both via hypothalamic neurons and by a direct action on pituitary thyrotrophs.     

Effect of central injection of bradykinin and bradykinin potentiating factor upon release of anterior pituitary hormones in ovariectomized female rats

The effects of third ventricular (IVT) injection of 25 μg of bradykinin (BK) upon plasma levels of LH, FSH, TSH, GH and prolactin were investigated in conscious ovariectomized female rats bearing indwelling jugular cannulae. Some animals were pretreated with bradykinin potentiating factor (BPF). Intravenous administration of BK had no effect upon hormone levels. IVT injection of BK significantly depressed plasma prolactin levels at 15 and 30 min post-drug, with levels returning to control values by 60 min. Pretreatment of animals with BPF (75 μg/3 μl) prolonged the prolactin suppression induced by BK for up to two hours. Plasma LH, FSH, TSH and GH levels in BK-rats were not significantly different from those of saline-injected animals at any time point measured. Neither BPF alone nor in conjunction with BK had any effects upon plasma levels of TSH; however, BK plus BPF suppressed FSH concentrations at 75 min post-BPF, while BPF alone appeared to increase GH levels at 45 min. In vitro incubation of hemipituitaries with 0.083, 0.83 or 8.33 μg/ml BK had no effect upon the release of LH, TSH or prolactin compared to control values. However, the secretion of GH and FSH was suppressed by the lowest dose of BK tested. These results suggest that BK may play a physiological inhibitory role in the regulation of prolactin, which can be augmented by preventing its degradation, i.e. via BPF. The effect of the peptide seems to be mediated by the CNS since neither intravenous injection of BK nor in vitro incubation of pituitaries with the peptide modified prolactin release.     

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.     

Enhanced ghrelin secretion in rats with cysteamine-induced duodenal ulcers

Ghrelin, produced and secreted by the A-like cells of the stomach, stimulates growth hormone secretion, gastric motility, and food intake. Cysteamine inhibits the release of somatostatin and induces the formation of duodenal ulcers in rats. The present study was conducted to investigate the dynamics of ghrelin secretion in rats treated with cysteamine. Male Wistar rats (7 wk old) were administered three doses of cysteamine (400 mg/kg) orally; at 50 h after the first dose, duodenal ulcers were induced, and the plasma level of somatostatin and gastric density of somatostatin-immunoreactive cells were significantly reduced. The plasma total and active ghrelin levels were significantly higher in the cysteamine-treated rats than in the control rats, whereas the gastric ghrelin levels, number of gastric ghrelin-immunoreactive cells, and preproghrelin mRNA expression levels were significantly lower. Even at the time points of 2 and 10 h after the first dose of cysteamine, at which time no significant ulcer formation or antral neutrophil accumulation was yet noted, a significant increase in the plasma ghrelin level and decrease in the gastric ghrelin level were observed. Furthermore, although lansoprazole treatment attenuated the duodenal ulceration induced by cysteamine, the increase in the plasma level of ghrelin could still be demonstrated. Because an inverse correlation was found between the plasma ghrelin and somatostatin levels, the inhibition of somatostatin secretion may be associated with the increased ghrelin secretion. In conclusion, an increase in the plasma ghrelin level precedes the formation of duodenal ulcers in rats treated with cysteamine.     

Does alprazolam, in contrast to diazepam, activate alpha 2-adrenoceptors involved in the regulation of rat growth hormone secretion?

The conventional benzodiazepine diazepam and the novel triazolobenzodiazepine alprazolam were compared with respect to effects on growth hormone (GH) release in reserpine pretreated rats. The reserpine pretreatment was undertaken to eliminate brain monoaminergic influence on GH secretion, hence obtaining a low GH baseline from which a drug induced increase could be easily detected. Previous studies have indicated that activation of brain alpha 2-adrenoceptors is an indispensable prerequisite for GH release induced by other agents such as serotonin and opiate receptor agonists. In line with these findings, diazepam was found to induce GH release in reserpine pretreated rats only when the alpha 2-receptor agonist clonidine was simultaneously administered. In contrast, alprazolam caused a dose-dependent increase in plasma GH when given alone to reserpine pretreated rats. This effect of alprazolam was effectively antagonized by either of the two selective alpha 2-receptor antagonists yohimbine or idazoxane. The data indicate that alprazolam, but not diazepam, activates brain alpha 2-adrenoceptors involved in rat GH regulation. The possibility that an alpha 2-agonistic profile of alprazolam may contribute to the suggested effectiveness of the drug in the treatment of panic disorder is discussed.     

Somatostatin as a physiological regulator of pulsatile growth hormone secretion

Somatostatin plays an important role in the regulation of the episodic and ultradian rhythm of growth hormone (GH) secretion. Passive immunization of rats with specific antibodies to the 14 and 28 amino acid sequences caused a significant GH elevation. The fact that somatostatin antiserum was unable to block episodic GH surges indicates that this hormone's release must be regulated by a dual mechanism. Indeed, GH-releasing factor (GRF) seems to be instrumental in the maintenance of pulsatile GH secretion. Moreover, exogenous GRF induced a further GH increase predominantly during the period of active secretion. Neutralization of endogenous somatostatin eliminated this time-dependent effect, indicating that this peptide blocks periodical spontaneous GH release. Food deprivation and changes in glucose homeostasis virtually obliterate the ultradian GH rhythm. In this context, peripheral somatostatin seems to play an important role. Also the central GRF/somatostatin interplay is responsible for a short-loop feedback control on pituitary somatotrops.     

Differentiation between the somatostatin inhibition and the post-somatostatin rebound observed on growth hormone secretion in vitro

A rebound in growth hormone secretion following somatostatin treatment has been shown in several systems where somatostatin suppresses secretion of the hormone. We have developed an in vitro system in which isolated and cultured pituitary cells were perfused after mild trypsinization. After washing, these cells retained their sensitivity and secreted growth hormone (GH) in response to physiological activators (norepinephrine, dopamine, serotonin) or inhibitors (somatostatin) as well as pharmacological activators (PGE2). The variation in GH secretion occurred within a minute after commencement of the infusion and was as rapidly reversible and repeatable minutes later. During somatostatin infusion the GH secretion was not totally suppressed (residual secretion (mean +/- S.D.) 34 +/- 7%). After the infusion a rapid rebound in GH secretion occurred, reaching levels in excess of the pretreatment value of 138 +/- 13%. This rebound effect occurred at doses higher than (10(-10)M) but not at lower doses, even when significant inhibition was observed. The inhibitory effect is of greater magnitude than the rebound effect (rebound = inhibition X 57 +/- 7% (mean +/- S.D.)). Furthermore, rebound was not enhanced by prolongation of somatostatin infusion. These latter results indicate that the rebound in secretion cannot be explained on the sole basis of storage of intracellular GH during somatostatin infusion and in fact suggest the involvement of a process of GH degradation and/or an inhibition of GH synthesis.