Hexarelin [His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH2], a new GH-releasing peptide, is biologically active in male and female rats (original) (raw)
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Growth hormone-releasing activity of hexarelin in humans
European Journal of Clinical Pharmacology, 1994
Hexarelin is a new hexapeptide (His-D-2methyl-Trp-Ala-Trp-x)-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 .gg-kg -1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 rain and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng. ml -~ after 0, 0.5, 1 and 2 ~tg. kg -~, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUCc~180) were 0.135, 1.412, 2.918 and 3.695 ~tg-min-m1-1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (EDs0) were estimated using logistic regression. The calculated EDs0 values were 0.50 and 0.64 pg-kg -~ for Cm~ and AUC0_~s0, respectively. The corresponding ErnaxS were 55.1 ng. mk 1 and 3936 rig. min-m1-1, thus indicating that the effect after the 2 gg. kg ~ dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.
Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat
European Journal of Endocrinology, 1996
Torsello A, Grilli R, Luoni M, Guidi M, Ghigo MC, Wehrenberg WB, Deghenghi R, Müller EE, Locatelli V. Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat. Eur J Endocrinol 1996;135:481–8. ISSN 0804–4643 We have reported Hexarelin (HEXA), an analog of growth hormone-releasing peptide 6 (GHRP-6), potently stimulates growth hormone (GH) secretion in infant and adult rats. This study was undertaken to further investigate Hexarelin's mechanisms of action. In 10-day-old pups, treatments with HEXA (80 μg/kg, b.i.d.) for 3–10 days significantly enhanced, in a time-related fashion, the GH response to an acute HEXA challenge. Qualitatively similar effects were elicited in pups passively immunized against growth hormone-releasing hormone (GHRH) from birth. In adult male rats, a 5-day pretreatment with HEXA (150 μg/kg, b.i.d.) did not enhance the effect of the acute challenge, and the same pattern was present after a 5-day pretreatment in male rats with surgica...
Interaction of the growth hormone releasing peptide hexarelin with somatostatin
Clinical Endocrinology, 1997
OBJECTIVE Growth hormone releasing peptides (GHRPs) are potent growth hormone (GH) secretagogues. Their interaction with growth hormone releasing hormone (GHRH) has been studied extensively. Data on their interaction with somatostatin (SS) are limited. The aim of this study was to determine the effect of changing SS tone and the effects of SS withdrawal on the somatotroph response to hexarelin and GHRH, alone or in combination. In addition, we studied the effect of SS on the prolactin (PRL) and cortisol response to hexarelin. DESIGN Boluses of saline, hexarelin (1 mg/kg), GHRH-(1-29)-NH 2 (1 mg/kg) or hexarelin plus GHRH-(1-29)-NH 2 were administered intravenously 1 hour after the start of a 3-hour constant intravenous infusion of saline, SS(1-14) (20 mg/m 2 /h) (SS20) or SS(1-14) (50 mg/m 2 /h) (SS50). In a second group of studies, the same boluses as above were administered intravenously at the time of withdrawal of a 3-hour constant intravenous infusion of saline or SS20. In a subset of the second group of studies, saline, hexarelin (0. 5 mg/ kg) or GHRH-(1-29)-NH 2 (0. 5 mg/kg) was administered intravenously two hours before the withdrawal of the SS(1-14) infusion, which was administered at a higher dose of 50 mg/m 2 /h. Studies were performed in a random order. SUBJECTS Twelve healthy adult males (20. 3-34. 6 years) were studied. MEASUREMENTS Serum GH and PRL concentrations were measured by immunoradiometric assays. Serum cortisol concentrations were measured by radioimmunoassay. RESULTS Infusion of SS20 resulted in a significant reduction in the peak GH response to hexarelin, GHRH-(1-29)-NH 2 or hexarelin plus GHRH-(1-29)-NH 2 (P < 0. 05). The peak serum GH concentrations following the intravenous administration of the two secretagogues, separately or in combination, were reduced further by the higher dose of SS50, but these were not significantly different from their respective peak serum GH concentrations obtained during the infusion of SS20. The peak serum GH concentration following the intravenous administration of hexarelin plus GHRH-(1-29)-NH 2 remained large (52. 6 Ϯ 7. 2 mU/l; mean Ϯ SEM) despite the high dose of SS(1-14) (50 mg/ m 2 /h). SS(1-14) did not affect the PRL and cortisol response to hexarelin. Withdrawal of SS20 infusion at the time of intravenous bolus administration of hexarelin, but not GHRH-(1-29)-NH 2 or hexarelin plus GHRH-(1-29)-NH 2 , resulted in a significant increase in peak serum GH concentration (P ¼ 0. 03). The intravenous administration of hexarelin (0. 5 mg/kg) or GHRH-(1-29)-NH 2 (0. 5 mg/kg) during an intravenous infusion of SS50 resulted in a small GH response (peak concentrations 6. 8 Ϯ 3. 6 mU/l and 2. 4 Ϯ 0. 5 mU/l, respectively) but the later withdrawal of the infusion was not followed by a rise in serum GH concentrations. CONCLUSIONS This study shows that SS and hexarelin counteract their respective inhibitory and stimulatory action on GH secretion and provides further evidence for their interaction in vivo. The stimulatory effect of hexarelin on the lactotroph and the hypothalamo-pituitary-adrenal axis is unaltered by SS. Hexarelin plus GHRH are synergistic and have potent GH-releasing activity despite a high dose SS infusion. Withdrawal of SS enhances the GH response to hexarelin, which may reflect simultaneous endogenous GHRH release synergizing with hexarelin. A single cycle of pretreatment with hexarelin during SS infusion is insufficient to allow synthesis and storage of sufficient GH to influence its release following SS withdrawal. These findings add further to the data already gathered about GHRPs and their complex interaction with the main regulators of GH secretions.
Metabolism, 1997
The growth hormone (GH) response to GH-releasing hormone (GHRH) is strongly inhibited by previous administration of recombinant human GH (rhGH), likely as a consequence of a somatostatin-mediated GH negative autofeedback, Hexarelin (HEX), a synthetic hexapeptide belonging to the GH-releasing peptide (GHRP) family, possesses a GH-releasing activity greater than that of GHRH both in animals and in man. The mechanism of action of GHRPs is yet to be completely clarified, although concomitant actions at the pituitary and hypothalamic level have been hypothesized. To further clarify the mechanisms of action underlying the GH-releasing activity of HEX, in six normal young volunteers we studied the effects of rhGH (2 U intravenously [IV]) on the GH response either to GHRH (2 i~g/kg IV) or to HEX (2 i~g/kg IV) alone or combined with GHRH and/or pyridostigmine ([PD], 120 mg orally). The GH-releasing effect of HEX was higher than that of GHRH (area under the curve [AUC], 2,200.8-256.9 v 792.2 _+ 117.6 i~g/L/h, P < .001), whereas combined administration of the two substances induced a true synergistic effect, with GH release after HEX plus GHRH (4,259.2-+ 308.0 i~g/L/h) being higher (P < .02) than the arithmetic sum of the GH increases induced by each compound separately administered. After rhGH administration, the GH-releasing effect of HEX was blunted (1,468.9-+ 193.7 #g/L/h, P < .04; inhibition of 32.1%), whereas that of GHRH was nearly abolished (102.0 4-7.8 i~g/L/h, P < .02; inhibition of 86.1%). The GH response to combined administration of HEX and GHRH was also blunted by the previous rhGH bolus (3,070.6 ± 481.8 ixg/L/h, P < .02; inhibition of 26.7%). PD did not modify the GH-releasing effect of HEX either alone (2,456.8 ___ 317.5 i~g/L/h) or combined with GHRH (4,009.1 _ 360.8 Ixg/L/h). rhGH was again able to blunt the GH response to HEX combined with PD (1,619.3 4-237.9 i~g/L/h, P < .02), but failed to modify the GH response to HEX combined with GHRH and PD (4,548.4 4-698.0 f~g/L/h). In conclusion, these results demonstrate that rhGH administration only blunts the GH-releasing activity of HEX, but abolishes that of GHRH. The blunting effect of rhGH on the GH response to HEX is probably mediated by a concomitant reduction in the activity of GHRH-secreting neurons and an increase of somatostatinergic tone.
Journal of Endocrinological Investigation, 1999
Reduced cardiac mass and performances are present in GH deficiency and are counteracted by rhGH replacement. GH and IGF-I possess specific myocardial receptors and have been reported able to exert an acute inotropic effect. Synthetic GH secretagogues (GHS) possess specific pituitary and hypothalamic but even myocardial receptors. In 7 male volunteers, we studied cardiac performance by radionuclide angiocardiography after iv administration of rhGH or hexarelin (HEX), a peptidyl GHS. The administration of rhGH or HEX increased circulating GH levels to the same extent (AUC: 1594.6±88.1 vs 1739.3±262.2 μg/l/min for 90 min) while aldosterone and catecholamine levels did not change; HEX, but not rhGH, significantly increased cortisol levels. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP) and heart rate (HR) were unaffected by rhGH (62.4±2.1 vs 62.1±2.3%, 90.6±3.4 vs 92.0±2.5 mm Hg, 62.3±1.8 vs 66.7±2.7 bpm). HEX increased LVEF (70.7±3.0 vs 64.0±1.5%, p<0.03) without significant changes in MBP and HR (92.8±4.7 vs 92.4±3.2 mmHg, 63.1±2.1 vs 67.0± 2.9 bpm). LVEF significantly raised at 15 min, peaked at 30 min and lasted up to 60 min after HEX. These findings suggest that in man, the acute administration of Hexarelin exerts a short-lasting, positive inotropic effect. This effect seems GH-independent and might be mediated by specific GHS myocardial receptors.
Acute administration of hexarelin stimulates GH secretion during day and night in normal men
Clinical Endocrinology, 1997
The aim of this study was to investigate the effect of a bolus injection of hexarelin given in the morning during wakefulness and during nocturnal sleep in a group of normal adult men. DESIGN AND SUBJECTS Eight normal men, aged 21-33 years, of normal height and within 10% of ideal body weight were studied. All subjects received in random order saline or hexarelin (2 mg/kg) in the morning between 0800 and 0900 h after they had fasted overnight. The same experiments were performed during nocturnal sleep in the same subjects. Saline or hexarelin were injected within 30 minutes after the onset of sleep between 2300 and 2400 h. Sleep was recorded by visual inspection. MEASUREMENTS In all four test sessions blood samples were taken 30, 15 minutes and immediately before the injection of saline or hexarelin and then every 15 minutes for 2 hours. GH was measured by an immunoradiometric assay. All values are expressed as peak GH levels or as area under the curve (AUC) calculated by trapezoidal integration. RESULTS Mean peak GH concentrations after hexarelin during the morning (58 : 2 Ϯ 4 : 7 mg/l) (GH mg/ l x 2 = mU/l) were not different from those observed during sleep (61 : 2 Ϯ 4 : 3 mg/l). The rate of disappearance of GH from plasma was slower during sleep (t 1=2 ¼ 64 : 9 Ϯ 14 : 8 min) than during morning hours (t 1=2 ¼ 24:9 Ϯ 1 : 4 min, P < 0 : 01). Mean AUC responses to hexarelin during sleep (1466 Ϯ 145 mg.min/l) were significantly higher than during morning hours (903 Ϯ 94 mg.min/l, P < 0 : 001). CONCLUSIONS These results show that GH responsiveness to a growth hormone releasing peptide is preserved during the night. This could be exploited for diagnostic and/or therapeutic purposes.
Clinical Endocrinology, 1997
OBJECTIVES Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism underlying the strong GH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the GH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by inhibiting somatostatin release, on the GH response to various HEX doses. DESIGN We studied the GH release induced by various HEX doses (0 . 25, 0 . 5 and 2 . 0 mg/kg iv) and pyridostigmine (PD, 120 mg po), both alone and coadministered. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1 . 0 mg/kg iv) were also studied. SUBJECTS Six normal male volunteers, aged 24-30 years, were studied. MEASUREMENTS Serum GH was measured in duplicate by immunoradiometric assay. RESULTS The GH response to HEX administration was dose-dependent. In fact, the GH response to 0 . 25 mg/kg HEX (AUC, mean Ϯ SEM: 816 . 4 (235 . 6 mU/l/ 120 min) was lower, although not significantly, than that to 0 . 5 mg/kg HEX (2154 . 6 Ϯ 491 . 6 mU/l/120 min), which, in turn, was lower (p < 0 . 05) than that after 2 . 0 mg/kg HEX (4819 . 2 Ϯ 668 . 0 mU/l/120 min). The GH rise after GHRH (1299 . 2 Ϯ 222 . 8 mU/l/120 min) was lower (P < 0 . 05) than that after 2 . 0 mg/kg HEX, but not different from the responses to either 0 . 25 or 0 . 5 mg/kg HEX. PD induced a significant GH rise (559 . 0 Ϯ 129 . 8 mU/l/120 min, P < 0 . 05 vs saline), similar to that after 0 . 25 mg/kg HEX, and lower than those after both 0 . 5 and 2 . 0 mg/kg HEX (P < 0 . 05 and p < 0 . 01, respectively) and GHRH (p < 0 . 05). PD pretreatment enhanced the GH response to the lowest HEX dose (1961 . 4 Ϯ 253 . 8 mU/l/120 min, p < 0 . 05) in an additive way, but failed to modify the GH response to either 0 . 5 or 2 . 0mg/kg HEX (2753 . 6 Ϯ 444 . 6 and 5179 . 0 Ϯ 770 . 8 mU/l/120 min, respectively). Notably, the GH response to 0 . 25 mg/kg HEX þ PD was still lower (P < 0 . 05) than that to 2 . 0 mg/kg HEX. PD pretreatment as well as 0 . 25 mg/kg HEX truly potentiated the GH response to GHRH to the same extent (4926 . 6 Ϯ 912 . 8 mU/l/120 min, p < 0 . 05 and 5958 . 8 Ϯ 750 . 0 mU/l/120 min, p < 0 . 05 respectively). The GH responses to PD þ GHRH and 0 . 25 mg/kg HEX þ GHRH were similar to that after 2 . 0 mg/kg HEX alone. CONCLUSIONS Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic somatostatin release, these findings are consistent with the hypothesis that they act by antagonizing somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.
Lack of effect of hexarelin on TRH-induced TSH response in normal adult man
Journal of Endocrinological Investigation, 1998
The mechanism of action of the synthetic growth hormone (GH)releasing peptide hexarelin is not yet fully understood. Although a direct effect on pituitary cells has been demonstrated, the peptide is also active at hypothalamic level, where specific binding sites have been found. The observation that hexarelin acts synergistically with GH-releasing hormone (GHRH) in releasing GH has suggested that it might suppress endogenous somatostatin secretion. As somatostatin is also inhibitory on TSH secretion, to verify the occurrence of modifications of the somatostatinergic tone induced by hexarelin, we studied its effects on TRHinduced TSH secretion. Seven normal subjects (4 women and 3 men aged 24-29 years) underwent the following tests on 3 different days: a) TRH (200 ~g/l iv)+placebo; b) hexarelin (1 ~g/Kg bw iv) +placebo c) combined TRH+hexarelin administration. Hexarelin induced significant and similar increases in serum GH levels when given in combination ei
European journal of Pharmacology, 1998
Growth hormone-releasing peptides (GHRPs) are a class of small peptides that stimulate growth hormone (GH) release in several animal species, including the human. Moreover, GHRPs injected into the brain ventricles stimulate feeding in the rat. The aim of this study was to evaluate the GH-releasing properties of a series of novel GHRP analogs and the possible existence of functional correlations between the GH-releasing activity and the effects on feeding behavior. Two well-known hexapeptides, GHRP-6 and hexarelin, given s.c., dose dependently stimulated both GH release and feeding behavior in satiated rats. However, in a series of tri-, penta- and hexapeptide analogs of hexarelin, some compounds were active either on GH release or on eating behavior. Interestingly, even minor structural modifications resulted in major changes of the pharmacological profile. We conclude that GHRPs have orexigenic properties after systemic administration which are largely independent from the effects they exert on GH release.