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Dipeptide preparation Noopept prevents scopolamine-induced deficit of spatial memory in BALB/c mice.
Bull Exp Biol Med
A P Belnik, R U Ostrovskaya, I I Poletaeva
The effect of original nootropic preparation Noopept on learning and long-term memory was studied with BALB/c mice. Scopolamine (1 mg/kg) impaired long-term memory trace, while Noopept (0.5 mg/kg) had no significant effect. Noopept completely prevented the development of cognitive disorders induced by scopolamine (blockade of muscarinic cholinergic receptors). Our results confirmed the presence of choline-positive effect in dipeptide piracetam analogue Noopept on retrieval of learned skill of finding a submerged platform (spatial memory). We conclude that the effectiveness of this drug should be evaluated in patients with Alzheimer's disease.
Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice.
FASEB J
Masashi Nakatani, Yuka Takehara, Hiromu Sugino +9 more
Myostatin is a potent negative regulator of skeletal muscle growth. Therefore, myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. The known myostatin inhibitors include myostatin propeptide, follistatin, follistatin-related proteins, and myostatin antibodies. Although follistatin shows potent myostatin-inhibiting activities, it also acts as an efficient inhibitor of activins. Because activins are involved in multiple functions in various organs, their blockade by follistatin would affect multiple tissues other than skeletal muscles. In the present study, we report the characterization of a myostatin inhibitor derived from follistatin, which does not affect activin signaling. The dissociation constants (K(d)) of follistatin to activin and myostatin are 1.72 nM and 12.3 nM, respectively. By contrast, the dissociation constants (K(d)) of a follistatin-derived myostatin inhibitor, designated FS I-I, to activin and myostatin are 64.3 microM and 46.8 nM, respectively. Transgenic mice expressing FS I-I, under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. Hyperplasia and hypertrophy were both observed. We crossed FS I-I transgenic mice with mdx mice, a model for Duchenne muscular dystrophy. Notably, the skeletal muscles in the mdx/FS I-I mice showed enlargement and reduced cell infiltration. Muscle strength is also recovered in the mdx/FS I-I mice. These results indicate that myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy.
Selank and its metabolites maintain homeostasis in the gastric mucosa.
Bull Exp Biol Med
T S Pavlov, G E Samonina, Z V Bakaeva +2 more
Antiulcer properties of a synthetic anxiolytic Selank and in vivo formed metabolites of this compound were studied on 3 experimental models of ulceration. The test peptides decreased the area of experimental gastric ulcers.
Loss of muscle strength during aging studied at the gene level.
Rejuvenation Res
Geoffrey Goldspink
Age-related muscle wasting and increased frailty is a major socioeconomic as well as a major medical problem. In our quest to extend the quality of life it is important to increase the strength of elderly people sufficiently so they can carry out everyday tasks and prevent them falling and breaking bones that are brittle because of osteoporosis. Muscles generate the mechanical strain that contributes to the maintenance of other musculoskeletal tissues and a vicious cycle is established when the muscles start to produce less force resulting in more bone loss and weakening of tendons. Another aspect that is less well appreciated is that muscle acts as a dynamic, metabolic store. In a traumatic situation, muscle provides amino acids to aid tissue repair processes and maintaining acid-base balance. At the present time there are strategies in addition to exercise for preventing age-related muscle wasting and these are briefly reviewed. Here, more attention is paid to the role of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and the discovery of mechano-growth factor (MGF). This is derived from the IGF-1 gene by alternative splicing and in the young is responsible for increasing contractile strength in response to exercise by activating the muscle satellite (stem) cells that kick-start local muscle repair and induce hypertrophy. Recent studies including gene transfer of this part of the IGF-1 gene and unique MGF peptides offer the prospect of treating muscle wasting during the aging process as well as muscle cachexia associated with many diseases.
The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer's disease model.
J Psychopharmacol
Rita U Ostrovskaya, Marina A Gruden, Natalya A Bobkova +7 more
The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Abeta peptide brain levels. In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Abeta((25-35)) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA). Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Abeta((25-35)) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Abeta((25-35)) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity. Enhancement of the immune response to Abeta((25-35)) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with its previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases.
Melanocortin receptors, melanotropic peptides and penile erection.
Curr Top Med Chem
Stephen H King, Alexander V Mayorov, Preeti Balse-Srinivasan +3 more
Penile erection is a complex physiologic event resulting from the interactions of the nervous system on a highly specialized vascular organ. Activation of central nervous system melanocortinergic (MC) receptors with either endogenous or synthetic melanotropic ligands may initiate and/or facilitate spontaneous penile erection. While the CNS contains principally the MC3 and MC4 receptor subtypes, there is conflicting data as to which receptor mediates erection. Although the MC4R is emerging as the principle effector of MC induced erection, the role of the MC3R is poorly understood. Manipulation of each receptor subtype with newly synthesized receptor specific agonists and antagonists, as well as knockout mice, has elucidated their individual contributions. Novel data from our laboratories suggests that antagonism of forebrain MC3R may enhance melanocortin-induced erections. Furthermore, melanocortin agents may interact with better-studied systems such as oxytocinergic pathways at the hypothalamic, brainstem or spinal level. Current therapies for erectile dysfunction target end organ vascular tissue. Manipulation of MC receptors may provide an alternative, centrally mediated therapeutic approach for erectile and other sexual dysfunctions. The non-specific "superpotent" MC agonist, PT-141, which is the carboxylate derivative of MT-II, has reached phase II human trials. Through their centrally mediated activity, melanocortin agonists have potential to treat erectile dysfunction as well as possible applications to the unmet medical needs of decreased sexual motivation and loss of libido.
Naloxone-blocked depriming effect of anxiolytic selank on apomorphine-induced behavioral manifestations of hyperfunction of dopamine system.
Bull Exp Biol Med
V K Meshavkin, N V Kost, O Yu Sokolov +3 more
Peptide anxiolytic selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) applied intraperitoneally in doses of 0.01, 0.1, 1.0, and 10.0 mg/kg to mice reduces behavioral manifestations of dopaminergic system induced by apomorphine in the verticalization test. This effect was comparable to that of atypical antipsychotic olanzapine in near-therapeutic doses (0.1 and 1.0 mg/kg, intraperitoneally) and was blocked with nonselective opioid receptor antagonist naloxone (10 mg/kg, intraperitoneally). Radioreceptor assay showed that selank did not displace nonselective D2-dopamine receptor antagonist (3)H-spiperone (EC50>100 microM) and delta- and micro-opioid receptor ligand 3H-DADLE (EC50>40 microM) from specific binding sites on rat brain membranes. It is hypothesized that the revealed behavioral effect of selank is mediated by its modulating effect on the endogenous opioid system and specifically, by its effect on activity of enkephalin-degrading enzymes.
Characterization of ghrelin receptor activity in a rat pituitary cell line RC-4B/C.
J Mol Endocrinol
H Douglas Falls, Brian D Dayton, Dennis G Fry +6 more
Ghrelin, a 28 amino acid, octanoylated peptide, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). In addition to various endocrine functions, including stimulation of GH release, ghrelin has been characterized as an important regulator of energy homeostasis. Ghrelin administration has been shown to increase adiposity in rodents and stimulate food intake in humans. Studies suggest that these orexigenic effects are mediated primarily through GHS-R expression in hypothalamic and pituitary neuronal pathways. In this context, GHS-R has been recognized as a potential target for the treatment of GH deficiency and body weight disorders. Cell lines provide convenient in vitro systems to identify and characterize potential pharmacophores and to analyze GHS-R functional activity. While recombinant cell lines that overexpress GHS-R have served as effective research tools for these studies, such cell lines may differ in signaling response to ghrelin compared with hypothalamic or pituitary cells expressing GHS-R. We show here that a cell line derived from a rat anterior pituitary adenoma, RC-4B/C, expresses endogenous GHS-R as judged by reverse transcriptase-PCR. In a Ca(2+)mobilization assay, RC-4B/C cells demonstrate a dose-dependent increase in intracellular [Ca(2+)] on stimulation with rat ghrelin and a related peptide agonist, hexarelin (EC(50), 1.0 nM and 1.7 nM respectively), but are unresponsive to treatment with inactive des-octanoyl rat ghrelin. A subclone, RC-4B/C.40, with a more robust and stable ghrelin response, was isolated from the parental population of cells to allow further analysis of GHS-R signal transduction. Using pertussis toxin and the phospholipase C inhibitor U-73122, we show that ghrelin signals through the Gq pathway in the RC-4B/C.40 cells. We also demonstrate that the ghrelin-induced rise of intracellular [Ca(2+)] in RC-4B/C.40 cells involves initial Ca(2+)release from intracellular stores followed by a sustained elevation that occurs via influx of extracellular Ca(2+) through ion channels. In addition, unlike observations reported in recombinant cell systems, the RC-4B/C.40 cells do not exhibit a high level of GHS-R constitutive activity as determined in a phosphatidylinositol hydrolysis assay. Overall, the data presented here suggest that the RC-4B/C parental and RC-4B/C.40 cells provide novel in vitro systems for the characterization of GHS-R pharmacophores and ghrelin signaling.
Role of serum myostatin during the lactation period.
J Reprod Dev
Tohru Hosoyama, Keitaro Yamanouchi, Masugi Nishihara
Myostatin, also known as GDF-8 (Growth/Differentiation Factor-8), is a member of the TGF-beta superfamily that negatively regulates skeletal muscle mass in mammals. Mutation of the myostatin gene in mice, cattle, and humans causes a massively developed skeletal muscle, characterized by muscle hypertrophy and hyperplasia. Although myostatin is predominantly expressed in skeletal muscle tissue, several recent studies have shown the presence of myostatin protein in blood and suggested a possible role for circulating myostatin in the regulation of skeletal muscle mass. In the present study, we examined changes in the levels of active form myostatin (13 kDa) in serum after birth by Western blot analysis to predict the role of serum myostatin in early postnatal muscle growth in the rat. Interestingly, the amount of active form myostatin in serum increased after birth and then decreased along with ageing after weaning. To clarify the role of increased serum myostatin during the postnatal period, we administrated follistatin, an inhibitor of myostatin activity, into postnatal rats intraperitoneally just after birth. Follistatin-administration during the postnatal period caused selective hypertrophy of type II muscle fibers in the soleus muscle. These results demonstrate that myostatin in serum acts on skeletal muscle and negatively regulates early postnatal muscle growth.
Influence of long-term treatment with tuftsin analogue TP-7 on the anxiety-phobic states and body weight.
Pharmacol Rep
Róza Czabak-Garbacz, Beata Cygan, Lukasz Wolański +1 more
TP-7 is a synthetic analogue of tuftsin. It has a structure of tuftsin, to which three natural L-amino-acids Pro-Gly-Pro are attached. This heptapeptide improves learning and memorization and causes antidepressant and anxiolytic effect. It is possible to use TP-7 in the future to optimize cognitive functions and as a potential new anxioselective, fast-acting and easy-dosed drug. Therefore, it was purposeful to study such properties of the heptapeptide as its influence on anxiety-fear and body weight under a long-term treatment regimen. The experiment was performed on 24 preselected Wistar rats with the use of Rodina's method. There were three experimental groups of animals with high initial emotional reactivity: passive control group (P), active control group (A, receiving distilled water) and group treated with TP-7 at the dose of 0.3 mg/kg (T). The rats of A and T groups received intraperitoneal injections every day. The experiments were conducted 15 min after the administration of the drug, one and two days after initial testing day, then 1, 2, 3 and 4 weeks after that. The heptapeptide reduced the anxiety-phobic states significantly starting from the second day of drug application. The observed effects persisted throughout four weeks of the experiment, which confirmed effective long-term anxiolytic properties of the heptapeptide. TP-7 did not cause any changes in the body mass by itself.
Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog.
J Clin Endocrinol Metab
Madalina Ionescu, Lawrence A Frohman
Pulsatile GH secretion is considered important for many of the hormone's physiological effects. Short-term GHRH infusions enhance GH pulsatility and increase IGF-I, but the short GHRH half-life limits its therapeutic use. A synthetic GHRH analog (CJC-1295) that binds permanently to endogenous albumin after injection (half-life = 8 d) stimulates GH and IGF-I secretion in several animal species and in normal human subjects and enhances growth in rats.
The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole.
Eur J Neurosci
Stephanie K Thacker, Marla K Perna, Jeffery J Ward +4 more
Male and female Sprague-Dawley rats were administered quinpirole (1 mg/kg, i.p.) or saline once daily from postnatal day (P)1 to P21. This drug treatment has been shown to produce long-term priming of the D2 receptor. Beginning on P62, rats were administered the atypical antipsychotic olanzapine (2.5 mg/kg) or saline twice daily (i.p.) for 28 days. One day after olanzapine treatment ceased, rats were tested on the place and match-to-place versions of the Morris water maze (MWM) for seven consecutive days. Dopamine D2 receptor priming was verified through a yawning behavioural test, a D2 receptor-mediated event, before olanzapine was administered as well as after olanzapine treatment and behavioural testing were complete. Results showed that neonatal quinpirole treatment induced D2 priming that was eliminated by olanzapine treatment. On the MWM place version, D2-primed rats demonstrated a significant impairment that was eliminated by olanzapine treatment, but olanzapine treatment to animals neonatally treated with saline produced a significant deficit on the place version of the MWM. There were no significant deficits on the match-to-place version. Brain tissue analyses revealed that neonatal quinpirole treatment produced a significant decrease in hippocampal NGF, BDNF and ChAT that was eliminated by olanzapine treatment. Neonatal quinpirole treatment produced a significant decrease in BDNF and ChAT in the frontal cortex that was unaffected by olanzapine treatment. These results show that olanzapine eliminates D2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D2 priming in the hippocampus.
Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse.
Am J Physiol Endocrinol Metab
Maria Alba, Danilo Fintini, Alessia Sagazio +4 more
Although the majority of children with isolated growth hormone (GH) deficiency have a good growth response to GH-releasing hormone (GHRH), the use of this therapeutic agent is limited by its very short half-life. Indeed, we have shown that, in mice with GHRH gene ablation (GHRH knockout; GHRHKO), even twice-daily injections of a GHRH analog are unable to normalize growth. CJC-1295 is a synthetic GHRH analog that selectively and covalently binds to endogenous albumin after injection, thereby extending its half-life and duration of action. We report the effects of CJC-1295 administration in GHRHKO animals. Three groups of 1-wk-old GHRHKO mice were treated for 5 wk with 2 microg of CJC-1295 at intervals of 24, 48, and 72 h. Placebo-treated GHRHKO mice and mice heterozygous for the GHRHKO allele served as controls. GHRHKO animals receiving daily doses of CJC-1295 exhibited normal body weight and length. Mice treated every 48 and 72 h reached higher body weight and length than placebo-treated animals, without full growth normalization. Femur and tibia length remained normal in animals treated every 24 and 48 h. Relative lean mass and subcutaneous fat mass were normal in all treated groups. CJC-1295 caused an increase in total pituitary RNA and GH mRNA, suggesting that proliferation of somatotroph cells had occurred, as confirmed by immunohistochemistry images. These findings demonstrate that treatment with once-daily administration of CJC-1295 is able to maintain normal body composition and growth in GHRHKO mice. The same dose is less effective when administered every 48 or 72 h.
Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization.
Peptides
Mac E Hadley, Robert T Dorr
The melanocortins (MCs) are a family of multifunctional peptidergic hormones. Several superpotent, prolonged acting, enzymatically resistant, MC analogs have been designed and synthesized to help clarify the nature and role of MCs and their receptors (MCRs) in physiological functions. Two of these analogs, a linear peptide, melanotan I, and a cyclic truncated peptide, melanotan II (MTI and MTII, respectively) have been patented and tested clinically for studies on tanning of the skin (MTI) and for diagnosis and treatment of male erectile dysfunction (MTII). A new MTII analog, PT-141 (Palatin Technologies) has initial phase I/II trials and is scheduled to enter pivotal stage III clinical trials leading to commercialization. MTI may provide a therapeutic tan with the potential to lower the risk of skin cancer. PT-141 may improve sexual functionality in both males and females.
Seabream ghrelin: cDNA cloning, genomic organization and promoter studies.
J Endocrinol
Chung-Man Yeung, Chi-Bun Chan, Norman Y S Woo +1 more
Recent studies have indicated that ghrelin stimulates growth hormone release from the pituitary via the growth hormone secretagogue receptor (GHSR). We have previously isolated two GHSR subtypes from the pituitary of the black seabream Acanthopagrus schlegeli. In the present study, we have cloned and characterized ghrelin from the same fish species at both the cDNA and gene levels. The full-length seabream ghrelin cDNA, isolated from sea-bream stomach using a novel approach by exploiting a single conserved region in the coding region, was found to encode a prepropeptide of 107 amino acids, with the predicted mature ghrelin peptide consisting of 20 amino acids (GSSFLSPSQKPQNRGKSSRV). Embedded in this full-length cDNA is a putative fish orthologue of the recently reported mammalian obestatin peptide. The ghrelin gene in black seabream, obtained by genomic PCR, was found to encompass four exons and three introns, possessing the same structural organization as in tilapia and goldfish, but different from that in rainbow trout. In addition, a 2230-bp 5'-flanking region of the seabream ghrelin gene was obtained by genome walking. Sequence analysis revealed that, as in the case of the human ghrelin gene, there is neither a GC box nor a CAAT box present in the isolated 5'-flanking region. However, a number of putative transcription factor-binding sites different from the human counterpart were found in the 5'-flanking region of the seabream ghrelin gene, suggesting that different cis- and trans-acting elements are involved in controlling their gene expression. Functional activity of this 5'-flanking region was examined by cloning it into the pGL3-Basic vector upstream of the luciferase reporter gene and transfected into various cell lines. Positive promoter activity could only be recorded in the colon-derived Caco-2 cells, suggesting that the cloned 5'-flanking region represents the functional promoter of the seabream ghrelin gene, which exhibits tissue-specific promoter activity. Using reverse transcriptase PCR analysis, expression of ghrelin was detected only in the seabream stomach, but not in the other tissues examined, including the brain, gill, intestine, kidney, liver and spleen. This stomach-specific expression of ghrelin in seabream is subject to regulation, as administration of growth hormone or ipamorelin to the fish in vivo was demonstrated to enhance its expression. Reminiscent of the homologous upregulation found in the transcriptional control of the seabream GHSR gene, a similar homologous regulatory mechanism might also exist in controlling the expression of seabream ghrelin. The identification of both GHSR and ghrelin from a single fish species would facilitate our subsequent studies on the elucidation of the physiological functions of the ghrelin/GHSR system in teleost. The possible existence of obestatin in teleost opens up new research avenues on the somatotropic axis in fish.
Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults.
J Clin Endocrinol Metab
Sam L Teichman, Ann Neale, Betty Lawrence +3 more
Therapeutic use of GHRH to enhance GH secretion is limited by its short duration of action.
[Evenly tritium-labeled peptides and their in vivo and in vitro biodegradation].
Bioorg Khim
Iu A Zolotarev, A K Dadaian, O V Dolotov +19 more
Biologically active peptides evenly labeled with tritium were used for studying the in vitro and in vivo biodegradation of the peptides. Tritium-labeled peptides with a specific radioactivity of 50-150 Ci/mmol were obtained by high temperature solid phase catalytic isotope exchange (HSCIE) with spillover tritium. The distribution of the isotope label among all amino acid residues of these peptides allows the simultaneous determination of practically all possible products of their enzymatic hydrolysis. The developed analytical method includes extraction of tritium-labeled peptides from organism tissues and chromatographic isolation of individual labeled peptides from the mixture of degradation products. The concentrations of a peptide under study and the products of its biodegradation were calculated from the results of liquid scintillation counting. This approach was used for studying the pathways of biodegradation of the heptapeptide TKPRPGP (Selank) and the tripeptide PGP in blood plasma. The pharmacokinetics of Selank, an anxiolytic peptide, was also studied in brain tissues using the intranasal in vivo administration of this peptide. The concentrations of labeled peptides were determined, and the pentapeptide TKPRP, tripeptide TKP, and dipeptides RP and GP were shown to be the major products of Selank biodegradation. The study of the biodegradation of the heptapeptide MEHFPGP (Semax) in the presence of nerve cells showed that the major products of its biodegradation are the pentapeptide HFPGP and tripeptide PGP. The enkephalinase activity of blood plasma was studied with the use of evenly tritium-labeled [Leu]enkephalin. A high inhibitory effect of Semax on blood plasma enkephalinases was shown to arise from its action on aminopeptidases. The method, based on the use of evenly tritium-labeled peptides, allows the determination of peptide concentrations and the activity of enzymes involved in their degradation on a tg scale of biological samples both in vitro and in vivo.
Impairment of IGF-I gene splicing and MGF expression associated with muscle wasting.
Int J Biochem Cell Biol
Geoffrey Goldspink
The characterisation of a local tissue repair factor (mechano growth factor, MGF) that is produced by exercised and/or damaged muscle by differential splicing of the IGF-I gene provides understanding of how muscle is maintained in the young normal individual. Mechano growth factor, or MGF, is different to the systemic IGF-I as it has an insert of 49 base pairs in exon 5 that introduces a reading frame shift resulting in a C terminal peptide with unique properties. Muscle is a post-mitotic tissue and as cell replacement is not a means of tissue repair there has to be an efficient local repair mechanism otherwise the damaged cells undergo cell death. The extra nuclei for muscle repair and hypertrophy are provided by the muscle satellite (stem) cells. The pool of these stem cells is apparently replenished by the action of MGF, which is produced as a pulse following a mechanical challenge. Unfortunately, the production of MGF is deficient in certain diseases such as in the muscular dystrophies in which the mechanotransduction mechanism, which may involve the dystrophin complex, is defective. In elderly muscles, decreased levels of growth hormone apparently mean that there is less primary RNA transcript of the IGF-I gene to be spliced towards MGF. Consequently, there is an increasing inability to maintain muscle mass during ageing. Delivery of MGF and cDNA or peptide produces marked increases in the strength of normal as well as diseased muscle and, therefore, MGF has considerable potential as a generic means of treating muscle cachexia.
Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system.
Trends Endocrinol Metab
Ji-Min Cao, Huy Ong, Chen Chen
Ghrelin, a newly discovered endogenous hormone that is produced by the stomach, and synthetic peptides have been identified recently as potent growth-hormone secretagogues. This effect is exerted through interaction with a specific G-protein-coupled receptor, GHS-R1a, which is expressed mainly in the hypothalamus-pituitary complex. A study of the peripheral distribution of GHS receptors has shown that it is also present in cardiovascular tissue, which has led to the exploration of the cardiovascular functions of ghrelin and synthetic, growth-hormone-releasing peptides. These ligands have several cardiovascular activities, including a cardioprotective effect against myocardial ischemia, and vasoactive and cardiotropic effects in both experimental models and humans. These effects are mediated by the interaction of these ligands with binding sites, including GHS-1Ra, for which the signalling pathways are not documented fully. Identification of the cardiac and vascular binding sites for ghrelin and synthetic, growth-hormone-releasing peptides will provide new perspectives for treating cardiovascular diseases with these ligands.
[Effects of the new peptide anxiolytic drug selank on the cardiovascular system functioning and respiration in cats].
Eksp Klin Farmakol
T S Gan'shina, I I Kozlovskiĭ
The effects of the new heptapeptide anxiolytic drug selank (300 mg/kg, i.v.) on the arterial pressure (AP), cerebral blood flow, heart rhythm, respiration, and the AP depression induced by acetylcholine injections was recorded in narcotized male cats. Selank produced a 32 +/- 4.3% decrease in the AP for the first 1-3 min after injection. The drug also induced a 24 +/- 2.8% increase in the cerebral blood flow for the first 5 - 10 min upon injection and then the blood flow was gradually restored on the initial level. The heart rate and the respiratory rate were not affected by the drug injections. Nor did selank influence the AP depression in response to the acetylcholine introduction.