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Using unanesthetized young male and female beagle dogs, before and after a 2-day fast, we studied the effect of an i.v. infusion of 0.9% saline (5 ml/h), somatostatin (SS, 4 or 8 micrograms/kg/h), or pretreatment with pirenzepine (PZ, 0.6 mg/kg i.v.), a muscarinic cholinergic antagonist which allegedly releases SS, on the GH release evoked by acute administration of GHRH (2 micrograms/kg i.v.), hexarelin (HEXA), a member of the GH-releasing peptide family (250 micrograms/kg i.v.) or GHRH plus HEXA. In fasted dogs, GHRH delivered during saline infusion induced a clear-cut rise in plasma GH levels, significantly higher than that which it induced in fed dogs. In contrast, HEXA, although very effective in causing the release of GH, only slightly increased GH secretion in fasted dogs over that which it induced in fed dogs. Co-administration of GHRH plus HEXA into fed dogs induced a synergic GH response that further increased with fasting. The action of GHRH in fed dogs was abolished by the lower dose of SS, whereas SS at either dose was ineffective in suppressing the GH-releasing effect during fasting. Infusion of the lower dose of SS failed to counter the action of HEXA, either before or during fasting, whilst the higher SS dose partially reduced it in both conditions. In contrast to SS, PZ reduced the GH-releasing effect of GHRH and HEXA, both in the fed state and, though to a lesser extent, during fasting. Pirenzepine only slightly reduced the robust GH rise elicited by GHRH plus HEXA in fed dogs. The suppressive effect of PZ on the GH response to combined administration of the peptides was lowest in fasted dogs. These data show that: (1) fasting augmented the GH response to GHRH and (to a lesser degree) to HEXA; (2) SS inhibited the GH response to GHRH in the fed state, but not in the fasted state; (3) only the higher dose of SS partially reduced the GH stimulation by HEXA in either the fed or the fasted state; (4) PZ lowered the GH response to GHRH and to HEXA in both the fed and (to a lesser degree) the fasted state; (5) PZ did not modify the GH release due to the combined administration of GHRH and HEXA. It is suggested that: (1) during fasting the greatly enhanced GH response to GHRH alone or GHRH plus HEXA probably reflects an augmented GHRH secretion; (2) somatotrope refractoriness to SS may contribute to the enhanced GH secretion in states of calorie deprivation; (3) in contrast to a general belief, muscarinic cholinergic antagonists, e.g. PZ, do not act exclusively via release of SS, but probably also through inhibition of GHRH function.
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GH-releasing peptides (GHRPs), a class of small synthetic peptide and non-peptide compounds, act on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in both humans and other animals. GHRPs, like corticotropin-releasing hormone (CRH), also possess acute ACTH- and cortisol-releasing activity, although the mechanisms underlying the stimulatory effect of GHRPs on the hypothalamo-pituitary-adrenal (HPA) axis are still unclear. In recent years, studies in humans and other animals have provided evidence that the rebound GH rise which follows withdrawal of an infusion of somatostatin (SS) (SSIW) is due, at least in part, to the functional activation of GH-releasing hormone (GHRH) neurons of the recipient organism. Unexpectedly, in humans, SS infusion, at a dose inhibiting basal GH secretion, has been associated with an activation of the HPA axis, leading to the hypothesis that this response was mediated, at least in part, by a central nervous system ACTH-releasing mechanism activated by the SS-induced decrease in GH secretion. Interestingly, the rebound GH rise which follows SSIW was magnified by the administration, before SS withdrawal, of a GHRP, implying that the SSIW approach could also be exploited to investigate in vivo the functional interaction in the process of GH and/or ACTH/cortisol secretion between endogenous GHRH (and/or other ACTH-releasing mechanisms) and GHRPs. In the present study, six young beagle dogs were given, on different occasions, at the beginning and at the end of a 3-h i.v. infusion of SS or saline (SAL), a bolus of physiological SAL or a GHRP compound, EP51216. SSIW induced a GH rebound rise without affecting plasma cortisol concentrations, while the withdrawal of SAL infusion was ineffective on either hormone paradigm. Administration of EP51216 at the beginning of SAL infusion evoked release of both GH and cortisol, whereas EP51216 administration at the withdrawal of SAL infusion evoked somatotroph and cortisol responses which were reduced in amplitude and duration. SS infusion significantly reduced the secretion of GH elicited by EP51216 but did not affect the rise of plasma cortisol levels. Interestingly, SSIW resulted in a marked enhancement of the somatotroph and cortisol responses evoked by EP51216. The marked rise of plasma GH levels induced by the GHRP after SSIW recalled that occurring after acute combined administration of recombinant human GHRH and EP51216, implying that exogenously delivered GHRP had synergized with the endogenous GHRH release triggered by SSIW. In contrast, acute combined administration of GHRH and the GHRP induced a cortisol response not different from that induced by GHRP alone, indicating that endogenous GHRH release was not involved in the enhanced cortisol response following EP51216 administration after SSIW. Similarly, the direct involvement of endogenous CRH could be ruled out, since i.v. administration of ovine CRH after SSIW evoked cortisol peak levels not different from those evoked by CRH at the withdrawal of SAL infusion. In conclusion, enhancement of the GH response to EP51216 alone by SSIW, to an extent reminiscent of that following combined administration of GHRH and EP61216, reinforces the view that SSIW elicits release of endogenous GHRH. Further studies are indeed necessary for a better understanding of the mechanisms underlying the enhanced cortisol response, since from now on the involvement of endogenous GHRH or CRH can be ruled out.
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Nuffield Institute for Medical Research and Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford, 0X3 9DU
(Received 6 April 1978)
Growth hormone (GH) has been located in the ovine foetal pituitary gland by day 50 of gestation (Stokes & Boda, 1968). The concentration of GH in the plasma of foetal sheep is ten times higher than the postnatal value, increasing from 40 ng/ml on day 100 of gestation to 100–120 ng/ml on day 140 (Bassett, Thorburn & Wallace, 1970). After foetal hypophysectomy, the concentration of GH falls to < 2 ng/ml, indicating that it originates in the foetal pituitary gland (Wallace, Stacey & Thorburn, 1973). Labelled GH does not cross the ovine placenta (Wallace et al. 1973). After sectioning the foetal pituitary stalk, the concentration of GH in the foetal plasma drops to approximately 5 ng/ml (Wallace et al. 1973), which implies that the secretion of GH
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ABSTRACT
Somatostatin-14 (SRIF-14) inhibited, in a concentration-dependent manner, LH- and forskolin-stimulated cyclic adenosine monophosphate (cAMP) induction in porcine granulosa and luteal cells. The inhibitory effect of SRIF-14 on hormone-induced cAMP generation was more potent in porcine ovarian cells than in the GH-3 pituitary cell line. The inhibitory effect of SRIF-14 was impeded by neutralizing its biological activity with specific antiserum. Preincubation of luteal and granulosa cells with phorbol 12-myristate 13-acetate (PMA) enhanced LH- and forskolin-stimulated cAMP levels. SRIF-14 failed to inhibit LH- or forskolin-stimulated cAMP levels in cells preincubated with PMA. It is concluded that SRIF-14 inhibits hormone-stimulated cAMP induction in the porcine ovary. LH-induced protein kinase C activation may be physiologically important to alleviate the inhibitory effects of SRIF-14.
Journal of Endocrinology (1992) 134, 297–306
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somatostatin we should feel more comfortable with the reference to these ‘hypothalamic hormones’, well in keeping with the use of the words by Starling who described, indeed, activating and inhibiting effects of his tissue extracts in his 1905 Croonian lecture
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function in glucose homeostasis. These two hormones have diametrically opposite actions on glucose regulation, and consequently, the secretion of one hormone is controlled by the other one. δcells secreting somatostatin and PP cells secreting pancreatic
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Department of Pure and Applied Zoology, The University, Leeds, LS2 9JT
(Received 17 July 1975)
The tetradecapeptide growth hormone inhibiting factor (GIF), synthesized by Coy, Coy, Arimura & Schally (1973) and Rivier, Brazeau, Vale, Ling, Burgus, Gilon, Yardley & Guillemin (1973), is reported to inhibit growth hormone (GH) secretion in mammals both in vitro and in vivo. It reduces the basal serum GH levels in rats (Brazeau, Rivier, Vale & Guillemin, 1974) and also inhibits the basal release of GH from rat pituitary cells incubated in vitro (Grant, Sarantakis & Yardley, 1974). Growth hormone inhibiting factor abolishes the suckling-induced rise in plasma GH levels in rats (Chen, Mueller & Meites, 1974) and similarly reduces the l-DOPA-stimulated rise in plasma GH in dogs (Lovinger, Boryczka, Shackleford, Kaplan, Ganong & Grumbach, 1974). In man, GIF reduces the serum GH levels artificially raised by means of insulin-induced hypoglycaemia (Schally, Coy, Kastin, Tunbridge, Evered,
Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
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Department of Internal Medicine and & Medical Specialties (DIMI) and Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
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Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
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mass (the primary cause of the disease). Treatment with somatostatin analogs (SSAs) and/or dopamine agonists (DAs) may result in the inhibition of ACTH secretion by the pituitary adenoma and, therefore, represent attractive drugs for CD treatment
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addressed in gonadectomized rats ( Jansson et al . 1985 ). We therefore describe the consequences of neonatal administration of testosterone to female mice on the modulation of the GHRH–somatostatin (STT) hypothalamic system that controls GH release and
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Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
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Introduction Pancreatic islet contains four major types of endocrine cells, including α, β, δ and PP cells, which secret glucagon, insulin, somatostatin and pancreatic polypeptide, respectively. All types of pancreatic endocrine cells arise
