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Sermorelin, Growth Hormone Releasing Hormone (1-29), hGRF(1-29)NH2
A synthetic peptide analog of growth hormone-releasing hormone that stimulates the pituitary gland to secrete growth hormone.
Sauvant. D D; Kann. G G; Hervieu. J J; Mandran. N N; Disenhaus. C C
In a study with dairy goats, giving them the peptide GRF‑1‑29 under the skin and feeding them higher‑energy diets each boosted milk output, and together they added up. However, injecting the peptide under the skin was not as effective as the intravenous method used before.
Spicer. L J LJ; Enright. W J WJ
In a study on young cows, daily injections of a growth‑hormone‑releasing peptide (GRF‑1‑29) for almost three months did not change the amount of IGF‑I in the fluid around ovarian follicles, but it made the biggest follicles a bit larger and raised progesterone levels in medium‑sized follicles. Thyrotropin‑releasing hormone had no effect.
Liu. D M DM; Cuevas. J J; Adams. D J DJ
The effects of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP27 and PACAP38) on isolated parasympathetic neurons of rat intracardiac and submandibular ganglia were examined under voltage clamp using whole-cell patch-clamp recording techniques. VIP and PACAP (</= 10 nM) selectively and reversibly increased the affinity of nicotinic acetylcholine receptor channels (nAChRs) for their agonists resulting in a potentiation of acetylcholine (ACh)-evoked whole-cell currents at low agonist concentrations. VIP-induced potentiation was observed with either ACh or nicotine as the cholinergic agonist. The VIP- but not the PACAP-induced potentiation of ACh-evoked currents was inhibited by [Ac-Tyr1, D-Phe2]-GRF 1-29, amide (100 nM), a selective antagonist of VPAC1 and VPAC2 receptors; whereas the PACAP38- but not the VIP-induced potentiation was inhibited by 100 nM PACAP6-38, a PAC1 and VPAC2 receptor antagonist. The signal transduction pathway mediating VIP- and PACAP-induced potentiation of nicotinic ACh-evoked currents involves a pertussis toxin (PTX)-sensitive G-protein. Intracellular application of 200 microM GTPgammaS or GDPbetaS inhibited VIP-induced potentiation of ACh-evoked whole-cell currents. GTPgammaS alone potentiated ACh- and nicotine-evoked currents and the magnitude of these currents was not further increased by VIP or PACAP. The G-protein subtype modulating the neuronal nAChRs was examined by intracellular dialysis with antibodies directed against alphao, alphai-1,2, alphai-3 or beta G-protein subunits. Only the anti-Galphao and anti-Gbeta antibodies significantly inhibited the effect of VIP and PACAP on ACh-evoked currents. The potentiation of ACh-evoked currents by VIP and PACAP may be mediated by a membrane-delimited signal transduction cascade involving the PTX-sensitive Go protein.
Yuwiler. A A; Brammer. G L GL; Bennett. B L BL
The study examined how the brain peptide PACAP and related peptides affect melatonin‑making enzymes in rat pineal glands, and whether they work together with adrenaline‑type signals. It found that adrenaline‑like drugs are far more potent than the peptides, and that a GRF‑1‑29‑based compound used as a blocker did not change any of the effects.
Fry. D C DC; Madison. V S VS; Greeley. D N DN; Felix. A M AM; Heimer. E P EP; Frohman. L L; Campbell...
Solution structures were determined for a linear analogue of growth hormone releasing factor (GRF), and cyclic and dicyclic analogues in which the side chains of aspartyl and lysyl residues spaced at positions i-(i + 4) were joined to form a lactam. The four analogues were [Ala15]-GRF-(1-29)-NH2 and its cyclo8-12, cyclo21-25, and dicyclo8-12;21-25 derivatives. The peptides were studied in two solvent systems: 75% methanol/25% water at pH 6.0; and 100% water at pH 3.0. CD spectroscopy was used to assess the overall alpha-helical content. Nuclear magnetic resonance spectroscopy was used to determine the structures in more detail. Nearly complete proton resonance assignments were made for each of the peptides, in both solvents. Nuclear Overhauser effects were converted into distance constraints and applied in the molecular dynamics program CHARMM to evaluate the range of low-energy structures that satisfied the nmr data. In 75% methanol, all of the peptides are comprised of a single alpha-helical segment with fraying of one to three residues at each end. The linear analogue has a tendency to kink. In water, the analogues have two helical segments with flexible regions between them and at the termini of the peptides. The linear analogue is helical at residues 7-14 and 21-28. In the cyclo8-12 analogue, the N-terminal helical region extends to include residues 7-19, while the other helical region is slightly shortened. In the cyclo21-25 analogue, the C-terminal helical region is extended to include residues 19-28, while the N-terminal helical region is destabilized. The dicyclic analogue has the largest N-terminal helix, spanning residues 7-20, but its helical segment at residues 21-28 is not well ordered. All of the analogues exhibit substantial biological activity. The cyclic and dicyclic analogues show dramatically increased resistance to degradation during incubation with human plasma. The i-(i + 4) lactam, therefore, appears to be a synthetic means of stabilizing a local alpha-helical conformation, which may be of general use in the design of active, stable peptides.
Ogilvy-Stuart. A L AL; Wallace. W H WH; Shalet. S M SM
Cranial irradiation frequently results in growth hormone (GH) deficiency. Patients with radiation-induced GH deficiency usually remain responsive to exogenous growth hormone releasing hormone, implying radiation damages the hypothalamus rather than the pituitary. Little is known about the effect of cranial irradiation on the neuroendocrine control of GH secretion. This study was to determine the effect of cranial irradiation on somatostatin tone. Somatostatin tone was examined by manipulating cholinergic tone in young adults with radiation-induced GH deficiency and a control population. Each individual underwent three separate studies: the GH response to 100 micrograms GHRH-(1-29)-NH2 was assessed alone, and 60 minutes after pyridostigmine or pirenzepine. Eight young male adults with radiation induced GH deficiency following treatment in childhood for a brain tumour or acute lymphoblastic leukaemia, and ten healthy adult men were studied. Serum growth hormone was measured at 15-minute intervals throughout each of the three study periods. One of 10 controls and four of eight irradiated subjects had a peak GH level to GHRH analogue of less than 20 mU/l. After pretreatment with pyridostigmine, all subjects except one irradiated subject had a peak GH level of greater than 20 mU/l. Pretreatment with pyridostigmine and pirenzepine significantly modified the GH response to GHRH analogue within both groups (P < 0.0005). Pretreatment with pyridostigmine significantly enhanced the GH response to GHRH analogue (median (range) area under the curve, 9029 (1956-20940) mU/l/min in controls vs 1970 (628-3608) mU/l/min in the irradiated group) compared with GHRH analogue alone (1953 (512-16140) mU/l/min in control group vs 997 (266-3488) mU/l/min in the irradiated group). Pretreatment with pirenzepine significantly attenuated the GH response to GHRH analogue (552 (64-1274) mU/l/min in controls vs 305 (134-2726) mU/l/min in irradiated group). Between the groups there was no significant difference in GH area under the curve (AUC) after GHRH analogue alone. There was a significantly (P = 0.0014) greater increment of GH secretion after pyridostigmine and GHRH analogue compared with GHRH analogue alone (difference in AUC of pyridostigmine+GHRH analogue and GHRH analogue alone 6348 (696-12856) mU/l controls vs 542 (120-1340) mU/l in the irradiated group) and significantly (P = 0.033) greater suppression of GH secretion after pirenzepine and GHRH analogue compared with GHRH analogue alone (difference in AUC of GHRH analogue alone and pirenzepine+GHRH analogue 1644 (222-15205) mU/l in controls vs 479 (469-1623) mU/l in the irradiated group) in the control population compared with those who had received cranial irradiation in childhood. These data suggest that cranial irradiation reduces but does not abolish somatostatin (SRIH) tone and also reduces endogenous GHRH secretion. Although SRIH tone is reduced, it can be increased by cholinergic manipulation and is therefore not irreversibly fixed. This has possible implications if GHRH analogues were used to treat children with radiation induced GH deficiency.
Bai. J P JP
The objective of this study was to compare, in rat small intestinal and colonic enterocytes, subcellular distributions of activities degrading the large peptides, neurotensin, acetylneurotensin (8-13), GRF(1-29)NH2 (human growth hormone releasing factor fragment), (desNH2Tyr1,D-Ala2,Ala15)-GRF(1-29)NH2, insulin, and insulin B-chain. Proteolytic activities degrading individual peptides in the 10,000-g pellet, rich in intracellular organelles, 27,000-g pellet, rich in brush-border membrane, 100,000-g pellet, and 100,000-g supernatant, rich in cytosol, were determined and compared for both the small intestine and colon. In colonic fractions, the cytosol had highest activity (g protein)-1 degrading three out of four peptides tested, while in small intestinal fractions, the 27,000-g pellet had the highest activity (g protein)-1, degrading four out of five peptides tested. In both small intestine and colon, the cytosol had a higher percentage of total proteolytic activity degrading each of the above polypeptides and the highest insulin-degrading activity (g protein)-1. The results suggest that at pH 7.5, proteolytic activities (g protein)-1 in the fraction of subcellular organelles are much lower than those in cytosol and that cytosolic proteolytic activities degrading polypeptides and analogues are significant.
Bauer. C K CK; Falk. T T; Schwarz. J R JR
An endogenous inward-rectifying K+ current is described, which is present in native oocytes of some Xenopus laevis donors. Experiments were performed using defolliculated oocytes from donor frogs obtained from two different suppliers. In all oocytes from animals from one source, an inward-rectifying K+ current could be elicited with negative pulses from a holding potential of -20 mV in external solutions with a high K+ concentration. Increasing external K+ concentrations increased the amplitude of this current and shifted the reversal potential towards more positive potentials. In 118 mM KCl, the inward-rectifying K+ current partially inactivated between -20 and -80 mV and completely inactivated at more negative membrane potentials; 50% steady-state inactivation occurred near -50 mV. The time course of inactivation of the inward-rectifying current could be well fitted with two exponentials. The slow time constant had values of about 500 ms and was voltage independent. In contrast, the fast time constant and the time to reach the peak inward current decreased with more negative membrane potentials. Ba2+, Cs+, quinine (all 5 mM) and 50 mM tetraethylammonium partially blocked the inward-rectifying K+ current, whereas 10 mM 4-aminopyridine was without blocking effect. The oxidant chloramine-T blocked the inward-rectifying K+ current without slowing its inactivation.
Nowak. M M; Markowska. A A; Nussdorfer. G G GG; Tortorella. C C; Malendowicz. L K LK
In rats, a drug that blocks the natural peptide VIP (called GRF‑1‑29) lowered the hormone aldosterone but didn’t change ACTH or cortisol levels under normal conditions. When the rats were stressed by cold, the blocker reduced the usual rise in stress hormones, while it had no effect on stress caused by ether. This suggests VIP helps control aldosterone and is important for the body’s response to cold stress.
Morii. H H; Honda. S S; Ohashi. S S; Uedaira. H H
The formation of alpha-helical assembly by complexing biologically active peptides with de novo designed protein is described. The de novo designed protein described here is a cystine-linked 4-helix bundle protein constructed with 80 amino acid residues and forms a hydrophobic core region surrounded by 4 helices in an aqueous solution. The biologically active peptides, such as melittin and human growth hormone releasing factor, contain the sequences that are able to form amphiphilic helices. These peptides alone do not form the alpha-helix structure in a diluted solution with low ion strength. But on mixing with the designed helix bundle protein, the peptides are strongly bound to the protein with the induction of alpha-helical structure in the biologically active peptides. The content of induced alpha-helix is in accord with that estimated from the amphiphilic sequence. The results mean that a novel architecture composed of alpha-helices is formed. Fluorescent and temperature-scanning measurement revealed that the alpha-helical assembly is constructed with hydrophobic interaction. Also, it is shown by means of fluorescence depolarization that the assembly has a compact globular form corresponding to 1:1 complex.
Bai. J P JP; Chang. L L LL
GRF(1-29)NH2 is degraded mainly by dipeptidyl peptidase IV (DPP IV) in plasma, resulting in inactivated GRF(3-29)NH2. To understand whether improving stability of GRF(1-29)NH2 in the plasma will result in enhanced stability in intestinal mucosal cells, stability of GRF(1-29)NH2 and [desNH2Tyr1,D-Ala2,Ala15]-GRF(1-29)NH2 in rat intestine brush-border membrane and homogenate was examined. [desNH2Tyr1,D-Ala2,Ala15]-GRF(1-29)NH2, resistant to plasma DPP IV, was much more stable than GRF(1-29)NH2 in enterocytes. Gradient HPLC analysis, mass balance analysis and studies of inhibitor effects revealed that GRF(3-29)NH2 was the major metabolite of GRF(1-29)NH2 due to the action of DPP IV during incubation with brush-border membranes. It is concluded that the design of peptide analogues to resist plasma enzymes dramatically increases stability in intestinal epithelium.
Gajda. Paulina Marta PM; Holm. Niels Bjerre NB; Hoej. Lars Jakobsen LJ; Rasmussen. Brian Schou BS; D...
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Engström. K G KG; Ohlsson. L L
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Marotti. L A LA; Jayawickreme. C K CK; Lerner. M R MR
A receptor for vasoactive-intestinal-peptide (VIP)-related peptides was functionally characterized in a cell line derived from Xenopus melanophores using a recently described microtiter-plate-based bioassay. Activation of the melanophore VIP receptor by VIP or the peptides pituitary-adenylate-cyclase-activating polypeptide (PACAP 38), PACAP 27, and helodermin stimulated intracellular 3'-5' cyclic adenosine monophosphate (cAMP) accumulation and pigment dispersion in the cells. Helodermin, with an EC50 (concentration of peptide inducing half-maximal melanosome dispersion) of 46.5 pM, was the most potent activator of pigment dispersion, followed by PACAP 38 > VIP > PACAP 27. A similar order of potencies was observed for the peptides to induce cAMP accumulation. The responses to VIP agonists were selectively inhibited by the VIP antagonists PACAP-(6-27) and (N-Ac-Tyr(1)-D-Phe2)-growth-hormone-releasing factor[GRF](1-29)-NH2. Taken together, the results suggest that the melanophores express a VIP receptor that shares certain characteristics of, but also differs significantly from, other previously identified VIP receptors.
Connor. E E EE; Barao. S M SM; Douglass. L W LW; Zinn. S A SA; Dahl. G E GE
The study tested whether a single injection of a growth‑hormone‑releasing hormone (GRF‑1‑29) can predict how fast young bulls will grow and how much meat versus fat they will have later. They measured the bulls' growth‑hormone spikes after the injection and found that larger hormone spikes were linked to faster growth and leaner carcasses. The findings are specific to cattle breeding and do not provide direct guidance for human health or performance.
Kiaris. H H; Schally. A V AV; Varga. J L JL; Groot. K K; Armatis. P P
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Wester. T J TJ; Fiorotto. M L ML; Klindt. J J; Burrin. D G DG
Our objective was to examine the influence of feeding and endogenous GH secretion on circulating IGF-I in colostrum-deprived newborn pigs fed colostrum (n = 4), formula (control, n = 4), or water (n = 4). In another four formula-fed pigs, GH was ablated (GRF-A) with two intravenous injections of a GH releasing-factor antagonist (N-Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2. Blood was serially sampled in all pigs to measure plasma IGF-I and GH profiles. Feeding increased plasma IGF-I concentration two- to fourfold and decreased GH secretion. Despite a more than 80% decrease in the plasma GH in GRF-A pigs, the circulating IGF-I concentration was similar to that in control pigs. In colostrum-fed pigs, plasma IGF-I was higher than that in control pigs, despite equal nutrient intake and lower circulating GH. There were no differences in plasma IGF binding protein (IGFBP)-3 levels among the treatment groups. However, the relative abundance of plasma IGFBP-4 was lower, and that of IGFBP-1 higher, in unfed pigs than in any of the three fed groups. The plasma insulin concentration was not different among fed pigs, but it was lower in unfed pigs. Our results indicate that the circulating IGF-I concentration is more dependent on nutrient intake than on GH in newborn pigs, despite relatively high GH concentrations. However, because the nutrient content in the formula was designed to match that of colostrum, a factor other than nutrient intake and GH was responsible for the maximal increase in circulating IGF-I concentration observed in colostrum-fed pigs.
Chen. C C; Farnworth. P P; Petersenn. S S; Musgrave. I I; Canny. B J BJ; Clarke. I J IJ
The study shows that the peptide GHRP‑2 does not trigger the growth‑hormone‑releasing‑factor (GRF) receptor in pituitary cells, even when the human GRF receptor is added. Instead, it works through a different pathway, confirming that GHRP‑2’s effects on growth hormone are not mediated by the GRF receptor.
Takai. N N; Yoshida. Y Y; Shida. T T; Kondo. E E; Ueda. Y Y; Kiyama. H H; Tohyama. M M
Vasoactive intestinal polypeptide (VIP)-receptor mRNA was strongly expressed in the acinar cells in the submandibular gland but not in the sublingual gland. VIP-containing nerve fibres were richly distributed around acini in the submandibular gland but were rare around acini of the sublingual gland. In the submandibular gland, the chorda was stimulated at various frequencies (1-40 Hz) together with an infusion of (N-Ac-Tyr1, D-Phe2)-GRF(1-29)-NH2 (109 M), VIP antagonist, which reduced salivary flow from the submandibular gland only at high-frequency stimulation (> 20 Hz), and more markedly reduced the salivary protein concentration. When the chorda was continuously stimulated the antagonist reduced the salivary flow only during the initial 5 min. Exogenous VIP 10(-12) - 10(-8) M) infusion at the same time as chorda stimulation caused no increase in salivary flow, but the salivary protein concentration was increased in a dose-dependent manner. In the sublingual gland, neither VIP nor the VIP antagonist affected chorda-evoked salivary flow and protein concentration. Thus, endogenous VIP may play a part in the regulation of both fluid and protein secretion, especially of protein, evoked by chorda stimulation at high frequency in the submandibular gland. These phenomena occurred only in the initial phase of secretion. In the sublingual gland, it seems likely that VIP plays no part in the regulatory mechanism, at least with regard to salivary fluid secretion in the acinar cells.
Pozo. D D; Montilla. M L ML; Guerrero. J M JM; Calvo. J R JR
In the present study we show that the synthetic peptides [4-Cl-D-Phe6,Leu17]VIP and the growth hormone releasing factor (GRF) analog [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 inhibit in a competitive manner the specific [125I]VIP binding to both rat and mouse peritoneal macrophages. In rat peritoneal macrophages, the order of potency of the different peptides, as expressed by the IC50 values was: VIP (IC50 = 1.90 +/- 0.16 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 125.8 +/- 13.2 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 354.8 +/- 21.2 nM). In mouse peritoneal macrophages a similar pattern of potency was observed: VIP (IC50 = 1.58 +/- 0.12 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 110.8 +/- 10.7 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 251 +/- 19.2 nM). The behavior as VIP receptor antagonists of both [4-Cl-D-Phe6,Leu17]VIP and [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 in rat and mouse peritoneal macrophages was confirmed by: (a) the shift to the right of VIP dose-stimulated cyclic AMP production curves in the presence of the two antagonists; (b) the agreement between the order of efficacy of the two peptides in competition experiments with the corresponding inhibition of cyclic AMP production; (c) the inefficiency of the two antagonists on the stimulation of cyclic AMP production by the beta-adrenoceptor agonist isoproterenol, which indicates the specificity of the interaction; (d) the synergic effect of VIP on isoproterenol-stimulated cyclic AMP production was completely abolished by [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2, suggesting that both antagonists acted via specific VIP receptors. Moreover, propranolol, a beta-adrenoceptor antagonist, did not affect the VIP-stimulated cyclic AMP production and the antagonist role of [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2; (e) in cross-linking experiments, the intensity of the labeling of the [125I]VIP/receptor complexes was significantly lower with the antagonists than in the control experimental situation in both mouse and rat peritoneal macrophage membranes.