Silva Elipe. M V MV; Bednarek. M A MA; Gao. Y D YD
Human ghrelin, the first recognized natural ligand of growth hormone secretagogue growth hormone secretagogue receptors (GHS-Rs) (M. Kojima, H. Hosada, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, Nature, 1999, Vol. 402, pp. 656-660), consists of 28 amino acids of which Ser3 is modified by n-octanoylation. This new peptide hormone has been implicated not only in regulation of the GH secretion but also in regulation of food intake. The discovery of ghrelin opens up more opportunities to study the relationship of ghrelin with metabolic diseases. Until now, only mass spectometry analysis has been reported on the structure of ghrelin. NMR analysis is a suitable way to study if any tertiary structure of unbound ghrelin is present in solution. NMR studies were carried out on human ghrelin and its five truncated analogs. The full-length ghrelin and its fragments exhibited random coil behavior in aqueous solution. Additional studies were carried out on the shortest active segment of human ghrelin, which consists of the first five amino acids of the ghrelin sequence (M. A. Bednarek, S. D. Feighner, S.-S. Pong, K. K. McKee, D. L. Hreniuk, M. V. Silva, V. A. Warrem, A. D. Howard, L. H. Y. Van der Ploeg, and J. V. Heck, Journal of Medical Chemistry, 2000, Vol. 43, pp. 4370-4376), to compare the spectral features with their counterparts in the full-length ghrelin. The NMR data showed behavior similar to ghrelin except for two additional nuclear Overhauser effects (NOEs) between the Phe4 NH and the protons of the beta-methylene of Ser3. CD on human ghrelin and its short active analog in water were indicative of random coil peptides. Molecular modeling based on NMR data was carried out to probe which structural features were similar to growth hormone-releasing peptide-6 (GHRP-6), a hexapeptide that binds to GHS-R releasing GH and stimulating food intake. Modeling suggested some similarities, but they were not of a nature to account for binding properties of these compounds.
Dickson. S L SL; Leng. G G; Dyball. R E RE; Smith. R G RG
Evidence for a central site of action of growth-hormone-releasing peptide (GHRP-6) was sought by (1) counting the number of Fos-positive nuclei within the brain following intracerebroventricular or intravenous injection of peptide and non-peptide GH secretagogues and (2) characterizing the electrophysiological responses of neuroendocrine arcuate neurones (recorded in vivo) following intravenous injection of GHRP-6. Conscious male rates were chronically implanted with intracerebroventricular or intravenous catheters. Dense nuclear Fos staining was induced throughout the ventral arcuate nucleus of rats injected intracerebroventricularly with low doses of GHRP-6 but not in rats injected with the endogenous GH-releasing hormone GHRH or in vehicle-treated controls. The non-peptidyl GH secretagogues L-692,585 and L-692,429 also induced Fos expression in the arcuate nucleus, and the pattern of distribution was similar to that described for GHRP-6. No increase in Fos expression was observed in rats given a systemic injection of a high dose of GHRH. In pentobarbitone-anaesthetized male rats, the effects of intravenous injection of GHRP-6 on the electrical activity of arcuate neurones was predominantly excitatory for putative neuroendocrine cells and inhibitory for the remaining unidentified cells. These results suggest that (1) GHRP-6 and non-peptidyl GH secretagogues have a central site of action involving the activation of a subpopulation of arcuate neurones and (2) this action is not mimicked by the central or peripheral effects of GHRH.
Ahnfelt-Rønne. I I; Haahr. P M PM
Growth hormone releasing peptides (GHRP) are synthetic hexapeptides that physiologically stimulate GH release through two different pathways: 1) central and 2) direct action on somatotropic cells. Animal experiments and first clinical trials show that synthetic GHRP and synthetic analogues could be useful substitutes to recombinant GH in the treatment of GH deficiency, and in pathological conditions which may benefit from amplification of the GH-IGF I axis activity.
Cheng. K K; Chan. W W WW; Butler. B B; Wei. L L; Smith. R G RG
Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC50 value of 60 nM. Under the same conditions, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC50 values of 10(-8) and 5 x 10(-10) M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 microM. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin.(ABSTRACT TRUNCATED AT 250 WORDS)
Dickson. S L SL; Luckman. S M SM
In this study we investigated the neurochemical identity of the arcuate cells activated following GH-releasing peptide-6 (GHRP-6) injection by comparing, on consecutive sections, the distribution c-fos messenger RNA (mRNA) with that of mRNAs for peptides synthesized in arcuate cells, including neuropeptide Y (NPY), GH-releasing factor (GRF), tyrosine hydroxylase, POMC, and somatostatin. Rats bearing chronically implanted jugular catheters were injected with either 50 micrograms GHRP-6 or vehicle. Thirty minutes later they were terminally anesthetized and perfused with fixative. Paraffin-embedded sections of 7 microns thickness were processed using in situ hybridization for either c-fos mRNA or mRNAs for the neurochemical markers. In GHRP-6-treated rats the mean (+/-SEM) number of cells expressing c-fos mRNA in the arcuate nucleus (23 +/- 2 cells/section per rat; n = 5) was significantly higher than for vehicle-treated controls (2 +/- 1 cells/section per rat; n = 5; P < 0.001, Mann-Whitney U test). Superimposed camera lucida maps indicated that, in GHRP-6-injected rats, neurochemically identifiable cells expressing c-fos mRNA also express NPY mRNA (51 +/- 4%), GRF mRNA (23 +/- 1%) tyrosine hydroxylase mRNA (11 +/- 3%), POMC mRNA (11 +/- 2%), or somatostatin mRNA (4 +/- 1%). Thus, the majority of cells expressing c-fos mRNA following GHRP-6 injection are NPY and GRF-containing cells.
Peñalva. A A; Carballo. A A; Pombo. M M; Casanueva. F F FF; Dieguez. C C
His-DTrp-Ala-Trp-DPhe-Lys-NH2 (GHRP-6) is a synthetic compound that releases GH in a dose-related and specific manner in several species, including man. To further characterize the effects and mechanism of action of GHRP-6 on GH secretion, we assessed in normal man plasma GH responses to that hexapeptide 1) alone and in combination with exogenous GH-releasing hormone (GHRH) administration, 2) in a state of high endogenous somatostatinergic tone after atropine administration, and 3) in a state of low endogenous somatostatinergic tone induced by the cholinergic receptor agonist drug pyridostigmine or after insulin-induced hypoglycemia. We found a similar increase in plasma GH levels after the administration of either GHRP-6 (1 microgram/kg) or GHRH (1 microgram/kg); the areas under the curve (AUC) were (mean +/- SEM) 973 +/- 181 and 821 +/- 139, respectively. After combined GHRP-6 and GHRH administration, GH responses were considerably greater than those after either compound alone (4412 +/- 842; P < 0.01). Administration of the cholinergic receptor antagonist atropine (1 mg, im) completely prevented the GH responses to GHRP-6 (area under the curve, 103 +/- 14 vs. 815 +/- 156, respectively). On the other hand, pyridostigmine, a cholinergic agonist, slightly increased GH responses to GHRP-6 (P < 0.01 when comparing the AUC after pyridostigmine administration of 1571 +/- 151 and the AUC after administration of GHRP-6 alone of 815 +/- 156). Finally, combined GHRP-6 and insulin administration induced a much greater increase in plasma GH levels (AUC, 4047 +/- 327) than insulin alone (1747 +/- 229; P < 0.05) or GHRP-6 alone (1248 +/- 376; P < 0.05). Our results lend support to the view that GHRP-6-induced GH secretion is exerted through a non-GHRH-dependent mechanism. Furthermore, the fact that enhancement of somatostatinergic tone with atropine completely prevented the GH responses to GHRP-6, while pyridostigmine and insulin-induced hypoglycemia, which increased plasma GH levels by inhibiting hypothalamic somatostatin release, increased the same response suggest that although GHRP-6-induced GH secretion is dependent on the endogenous somatostatinergic tone, the stimulatory effect of GHRP-6 on plasma GH levels is not mediated by a change in hypothalamic somatostatinergic tone.
Torsello. A A; Grilli. R R; Luoni. M M; Guidi. M M; Ghigo. M C MC; Wehrenberg. W B WB; Deghenghi. R...
Hexarelin, a synthetic version of GHRP‑6, can trigger growth‑hormone release in rats. In young rats, giving it for several days makes the body respond more strongly to a later dose, but this “priming” effect isn’t seen in adult rats. The peptide seems to work in three ways: a small direct hit on the pituitary, by causing the brain to release the natural hormone‑releasing factor GHRH, and possibly by an unknown brain signal that works together with GHRH.
Lee. P I PI
The transient dynamic swelling and dissolution behavior during the release of a growth hormone releasing peptide, [D-Trp2-D-Phe5]GHRP, from erodible, non-cross-linked poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA) beads has been investigated at pH 7.4 as a function of buffer concentration. Although the swelling front penetration shows a ionization-limited behavior similar to that of nonerodible cross-linked PMMA/MAA beads, the normalized diameter of the polymer beads exhibits a brief initial rise followed by an extended linear decline due to establishment of the polymer dissolution process. This is consistent with the general kinetic scheme of dissolution of glassy polymers originally predicted for the slab geometry. In all cases, the initial gel thickness increases as a result of the ionization and swelling of the glassy PMMA/MAA beads. This is followed by an extended period of constant gel thickness due to the onset of polymer dissolution and the synchronization of movement of the swelling and dissolution fronts. The resulting constant gel layer thickness as well as the onset and duration of front synchronization shows an increasing trend with decreasing buffer concentrations. As a result, the corresponding peptide release is slower and the release duration longer at lower buffer concentrations. This is believed to be the first time that a synchronization of swelling and dissolution fronts has been documented for a spherical erodible sample. Although such synchronization of fronts does not result in a constant rate of peptide release due to the spherical geometry, some non-Fickian release characteristics have been observed.
Herrington. J J; Hille. B B
The actions of GH-releasing hexapeptide (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 or GHRP-6) on single rat somatotropes were studied using whole cell patch clamp electrophysiology and indo-1 Ca2+ photometry. GHRP-6 elevated intracellular free Ca2+ ([Ca2+]i) in two phases: a rapid transient phase, followed by a persistent phase. Based on its insensitivity to treatments that block Ca2+ entry [removal of external Ca2+, addition of the dihydropyridine Ca2+ channel blocker nitrendipine (1 microM), and the hyperpolarizing action of zero external Na+ or 100 nM somatostatin], the transient elevation is the result of release of Ca2+ from intracellular stores. The half-maximal concentration for the peak [Ca2+]i rise during Ca2+ release was 49 nM GHRP-6. Prior treatment of cells with caffeine (10 mM) or ryanodine (50 microM) abolished or partially occluded GHRP-6-induced Ca2+ release. Simultaneous measurement of [Ca2+]i and membrane current or potential revealed that the transient release of Ca2+ by GHRP-6 activates a voltage-independent Ca(2+)-activated K+ conductance, which transiently hyperpolarizes the somatotrope. The GHRP-6-induced persistent [Ca2+]i elevation is abolished by removal of external Ca2+ or external Na+ or the addition of 1 microM nitrendipine or 100 nM somatostatin, consistent with Ca2+ entry through voltage-dependent Ca2+ channels. In nondialyzed cells (perforated patch recording), we have identified a long-lasting GHRP-6-induced depolarization which may be responsible for the persistent [Ca2+]i elevation.
Pombo. M M; Barreiro. J J; Peñalva. A A; Mallo. F F; Casanueva. F F FF; Dieguez. C C
A study gave a single IV dose of the peptide GHRP‑6 to children with short stature to see if it could help diagnose growth hormone deficiency. The test didn’t reliably separate kids with true deficiency from those who just grew slowly, so it isn’t useful as a diagnostic tool.
Alster. D K DK; Bowers. C Y CY; Jaffe. C A CA; Ho. P J PJ; Barkan. A L AL
In patients with acromegaly, GH-producing pituitary tumors release GH in response to specific stimuli such as GH-releasing hormone (GHRH) and are also responsive to a variety of nonspecific stimuli, such as TRH or GnRH, and may exhibit paradoxical responses to glucose and dopamine. In healthy humans, the synthetic peptide GH-releasing peptide (GHRP) (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) releases GH by a putative mechanism of action that is independent of GHRH. How these tumors respond to GHRP is not well characterized. We studied the GH responses to GHRH, GHRP, and TRH stimulation in 11 patients with active acromegaly. The peak GH responses to GHRP and GHRH were not correlated (r = 0.57; P = 0.066). In contrast, the peak GH responses to GHRP and TRH were highly correlated (r = 0.95; P < 0.001). In conclusion, in patients with acromegaly, the GH response to GHRP is qualitatively normal and does not appear to depend on GHRH.
Ozata. Metin M; Dieguez. Carlos C; Casanueva. Felipe F FF
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Shu. A Y AY; Heys. J R JR
The paper explains how scientists made a radioactive version of the GHRP‑6 peptide for lab experiments. It focuses on chemistry tricks to attach tritium and verify its purity, not on how the peptide works in the body or how to use it for health or performance.
Huhn. W C WC; Hartman. M L ML; Pezzoli. S S SS; Thorner. M O MO
GH-releasing peptide (GHRP; SK&F 110679) is a synthetic hexapeptide that specifically stimulates GH release through nonopiate non-GH-releasing hormone (non-GHRH) receptors. To determine the effects of a 24-h GHRP infusion, eight normal young men received infusions of saline for 2 h, then saline (on two occasions) or GHRP (1.0 micrograms/kg.h; on two occasions) for 24 h, followed by an iv bolus of GHRP or GHRH (1.0 micrograms/kg) and a 2.5-h saline infusion. Serum GH was measured every 10 min throughout the 28.5-h period. GH secretion rates [per L distribution volume (Lv)] were determined by deconvolution analysis; attributes of pulsatile GH release were assessed by Cluster analysis. GH secretion was enhanced and remained pulsatile during GHRP infusions. The two GHRP infusions increased GH secretion rates (micrograms per Lv/h) 8-fold compared to saline (GHRP, 12 +/- 2.1 and 12 +/- 2.2; saline, 1.5 +/- 0.34 and 1.4 +/- 0.27; P < 0.05). The number of GH pulses, pulse duration and height, incremental pulse amplitude, interpeak valley concentration, and individual pulse areas were significantly greater during GHRP infusions than during saline treatment. Attributes of pulsatile GH release on the two GHRP infusion days were significantly correlated, indicating that enhancement of GH secretion by GHRP is highly reproducible. Mean plasma insulin-like growth factor-I (IGF-I) concentrations increased 12% and 22% on GHRP infusion days, whereas IGF-I levels declined 18% and 20% during saline infusions (P < 0.05). GHRP infusion significantly attenuated the GH response to a subsequent GHRP bolus injection; both GH secretion rates (GHRP, 4.1 +/- 1.6; saline, 19 +/- 3.0 micrograms/Lv.h; P < 0.05) and peak GH concentrations (GHRP, 7.9 +/- 2.9; saline, 25 +/- 2.9 micrograms/L; P < 0.05) were decreased. In contrast, peak GH concentrations in response to GHRH were significantly increased after GHRP infusion compared to those after saline treatment (24 +/- 4.7 vs. 11 +/- 2.7 micrograms/L; P < 0.05). We conclude that 24-h GHRP infusions augment pulsatile GH release and increase plasma IGF-I concentrations without significant adverse effects. Attenuation of the GH response to a subsequent GHRP bolus is not caused by depletion of pituitary GH, since the response to a GHRH bolus was enhanced by prior infusion of GHRP.
Jansson. J O JO; Svensson. J J; Bengtsson. B A BA; Frohman. L A LA; Ahlman. H H; Wängberg. B B;...
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Micioni Di Bonaventura. Emanuela E; Botticelli. Luca L; Del Bello. Fabio F; Giorgioni. Gianfabio G;...
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Santana. Héctor H; Avila. Cesar L CL; Cabrera. Ingrid I; Páez. Rolando R; Falcón. Viv...
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Popovic. Vera V; Pekic. Sandra S; Simic. Mirjana M; Damjanovic. Svetozar S; Micic. Dragan D; Dieguez...
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Bhatti. S F M SF; De Vliegher. S P SP; Van Ham. L L; Kooistra. H S HS
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Lawrence. Catherine B CB; Snape. Amelie C AC; Baudoin. Florence M-H FM; Luckman. Simon M SM
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