DOCSLIB.ORG

Pharmacokinetics and Pharmacodynamic Effects S3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pharmacokinetics and Pharmacodynamic Effects S3 Gut 1994; supplement 3: S 1-S4 Si Somatostatin and somatostatin analogues: effects pharmacokinetics and pharmacodynamic Gut: first published as 10.1136/gut.35.3_Suppl.S1 on 1 January 1994. Downloaded from A G Harris Abstract (amylase, trypsin, lipase). Octreotide Somatostatin is a 14 amino acid peptide increases intestinal transit time and that inhibits pancreatic exocrine and decreases endogenous fluid secretion in endocrine secretion. Its clinical applica- the jejunum and ileum, thus increasing tion has been limited by its very short half the absorption of water and electrolytes. life, necessitating continuous intravenous These pharmacological effects of the infusion. Octreotide is an 8 amino acid analogue point to its therapeutic role in a synthetic analogue of somatostatin that variety of endocrine and gastrointestinal possesses similar pharmacological effects. disorders. It has a much longer duration of action, (Gut 1994; supplement 3: SI -S4) however, and can be given subcuta- neously. Both the intravenous and sub- cutaneous routes ofinjection of octreotide The somatostatin family are well tolerated. Peak serum concentra- tions occur within 30 minutes after NATIVE MOLECULAR STRUCTURES subcutaneous administration and within Somatostatin is the name given to a family of four minutes of a three minute intra- peptides, the original member of which, venous infusion. Serum concentration somatostatin 14, a tetradecapeptide, was first increases linearly with dose. Octreotide is isolated from ovine hypothalami by Roger distributed rapidly, mainly in the plasma, Guillemin's group at the Salk Institute, in the where it is 65% protein bound. The course of an unsuccessful search for growth elimination half life is about 1.5 hours hormone releasing factor. The molecule was and about 32% of a subcutaneous dose shown to inhibit growth hormone release from is excreted in the urine as unchanged cultured pituitary cells, and for a while was octreotide. Octreotide inhibits gastro- known variously as growth hormone release enteropancreatic secretion, especially of inhibiting factor, somatotropin release inhibi- ting factor, and growth hormone release insulin, glucagon, pancreatic polypeptide, http://gut.bmj.com/ gastric inhibitory polypeptide, and inhibiting factor, until somatostatin - proposed gastrin. It also inhibits both release of by the Salk group in a note to the original thyroid stimulating hormone and article - emerged as standard. growth hormone secretion in response to The native molecule was found to have a Division Clinical exercise, insulin induced hypoglycaemia, cyclic structure joined by two intramolecular Pharmacology, and argenine stimulation. Octreotide disulphide bonds between the two cysteine Department of reduces splanchnic blood flow in healthy residues (Figure). The linear reduced on September 24, 2021 by guest. Protected copyright. Medicine, Cedars- Sinai Medical Center, volunteers and hepatic venous pressure in sequence, however, proved to have the same Los Angeles, cirrhotic patients. It can accelerate or biological activity as the cyclic form in vitro - California, USA delay gastric emptying, prolong transit that is, the cyclic form was not essential for A G Harris time at moderate to high doses, stimulate recognition by specific somatostatin receptors. Correspondence to: motility at low doses, and inhibit gall A second native form of somatostatin was Dr A G Harris, Division Clinical Pharmacology, bladder emptying. Octreotide consider- reported in 1980.2 Somatostatin 28 contains Department of Medicine, ably inhibits pentagastrin stimulated the amino acid sequence of somatostatin 14, Cedars-Sinai Medical Center, Los Angeles, gastric acid secretion and significantly extended by 14 residues at the N-terminus. California, USA. diminishes exocrine pancreatic function Though there is some evidence that somato- statin 28 may act as a precursor, it also operates as a hormone in its own right, with Human somatostatin Octreotide a slightly different spectrum of activity in different tissues. Thus somatostatin 28 suppresses growth hormone for much longer, but is less effective in suppressing gastric acid. There is virtually no somatostatin 28 in the stomach and duodenum. It has been shown, however, to be the dominant form lower down the gut.3 4 LOCALISATION Large amounts of somatostatin are found in Amino acids essential the gastrointestinal system, including the -4 for receptor binding pancreas, visceral autonomic nervous system, Amino acid composition ofsomatostatin and octreotide. endocrine cells, and gut lumen. Immuno- S2 Harmis cytochemical studies show that somatostatin is independent mechanisms29 30 and may act by localised to the D cells of the pancreas and gut affecting calcium transport through the cell mucosa, particularly in the gastric fundus, membrane.3' Because somatostatin inhibits antrum, and duodenum.5 6D cells are situated many aspects of cellular function, including Gut: first published as 10.1136/gut.35.3_Suppl.S1 on 1 January 1994. Downloaded from in the lower third of the crypts, from where endocrine secretion, muscular contraction, they extend cytoplasmic processes along the and cellular growth, it must antagonise a basal membranes to the basal pole of variety of intracellular signalling programmes. neighbouring glands.7 Thus somatostatin is The dephosphorylation processes crucial for well placed to exercise paracrine control of secretory activity intimately participate in other endocrine cells in the gut, for example, inhibition by somatostatin at the molecular those responsible for the synthesis and release level. After binding to its receptor, somato- of gastrin. The D cells also have microvilli in statin probably acts as a dephosphorylator to direct contact with the lumen, thus providing a inhibit secretory processes, but whether the pathway by which changes in gut content can hormone also interacts with DNA to affect influence somatostatin production, either into transcription is disputed. the lumen or into the circulation. In addition, Because of its many diverse physiological the gut is innervated by extrinsic and intrinsic effects, native somatostatin has been investi- somatostatin containing neurones, with the gated for the treatment of acromegaly and gut intrinsic neurones being present in both the endocrine tumours. Despite its many potential submucosal and myenteric plexuses. uses, however, the clinical applications of somatostatin were limited by a very short half life of two to three minutes, necessitating con- ACTIONS tinuous intravenous infusion and resulting in These anatomical considerations explain how rebound hypersecretion of hormones after somatostatin can have multiple endocrine, infusion. paracrine, and exocrine functions, in addition to its central growth hormone release inhibit- ing effect. The first description of its gastro- OCTREOTIDE intestinal action was published within a year of Octreotide (Sandostatin) is an 8 amino acid the original paper.8 Somatostatin has long synthetic peptide analogue engineered to recognised inhibitory effects on pancreatic overcome the limitations of native somato- endocrine and exocrine secretion - that is, on statin.32 Octreotide retains the Phe-Trp-Lys- insulin, glucagon, and pancreatic polypep- Thr portion of the native molecule (with the tide9 10 and also on pancreatic enzyme and tryptophan residue in the D configuration), bicarbonate responses to cholecystokinin and which is believed to constitute the essential secretin,l-13 recently reviewed by Layer et al. 14 pharmacophore22 23 and to be critical for gut It also inhibits the secretion of a wide variety of specificity.33 Octreotide has greater pharmaco- http://gut.bmj.com/ stimulatory gastrointestinal hormones,'5 and logical activity than the native molecule (being decreases gastrointestinal motility and blood at least 20 times more potent in suppressing flow.118 growth hormone secretion in vivo), is more selective for the inhibition of growth hormone than of insulin, and has a much enhanced STRUCTURE-FUNCTION RELATIONS duration of action (an elimination half life of The action of native somatostatin is brief and 113 minutes compared with the to two three on September 24, 2021 by guest. Protected copyright. rapid, and is followed by rebound secretion, all minutes of somatostatin).32 The synthetic of which suggests that it inhibits release rather molecule is sufficiently stable even to retain than synthesis, perhaps by depressing exocyto- some activity on oral administration, the oral sis. 19 dose required to inhibit growth hormone secre- Somatostatin receptors have been identified tion by 50% being 125 ,ug/kg after one hour.34 in the exocrine pancreas, on islet cells secreting As octreotide is incompletely absorbed insulin, glucagon and somatostatin,20 and on after oral administration, investigation of its gastric cells.2' Binding of somatostatin to its pharmacokinetic profile used intravenous and receptor is accounted for primarily by the 4 subcutaneous injection. Both routes of injec- amino acids in positions 7 to 10.22 23 In the late tion are well tolerated and the incidence of side 1970s analogues were synthesised that were effects is low. Moreover, bioavailability is more specific in some respects than the native similar by both routes of administration. Peak peptide, for example, more effective in inhibit- serum concentrations occur within 30 minutes ing insulin than glucagon, and vice versa,24 25 after subcutaneous administration and within while the structural requirements
Load more

Recommended publications
  • Searching for Novel Peptide Hormones in the Human Genome Olivier Mirabeau
    Searching for novel peptide hormones in the human genome Olivier Mirabeau To cite this version: Olivier Mirabeau. Searching for novel peptide hormones in the human genome. Life Sciences [q-bio]. Université Montpellier II - Sciences et Techniques du Languedoc, 2008. English. tel-00340710 HAL Id: tel-00340710 https://tel.archives-ouvertes.fr/tel-00340710 Submitted on 21 Nov 2008 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE MONTPELLIER II SCIENCES ET TECHNIQUES DU LANGUEDOC THESE pour obtenir le grade de DOCTEUR DE L'UNIVERSITE MONTPELLIER II Discipline : Biologie Informatique Ecole Doctorale : Sciences chimiques et biologiques pour la santé Formation doctorale : Biologie-Santé Recherche de nouvelles hormones peptidiques codées par le génome humain par Olivier Mirabeau présentée et soutenue publiquement le 30 janvier 2008 JURY M. Hubert Vaudry Rapporteur M. Jean-Philippe Vert Rapporteur Mme Nadia Rosenthal Examinatrice M. Jean Martinez Président M. Olivier Gascuel Directeur M. Cornelius Gross Examinateur Résumé Résumé Cette thèse porte sur la découverte de gènes humains non caractérisés codant pour des précurseurs à hormones peptidiques. Les hormones peptidiques (PH) ont un rôle important dans la plupart des processus physiologiques du corps humain.
    [Show full text]
  • DEPLETION of SOMATOSTATIN-LIKE IMMUNOREACTIVITY in the RAT CENTRAL NERVOUS SYSTEM by Cysteaminel
    0270~6474/82/0202-0225$02.00/O The Journal of Neuroscience Copyright 0 Society for Neuroscience Vol. 2, No. 2, pp. 225-231 Printed in U.S.A. February 1982 DEPLETION OF SOMATOSTATIN-LIKE IMMUNOREACTIVITY IN THE RAT CENTRAL NERVOUS SYSTEM BY CYSTEAMINEl STEPHEN M. SAGAR,2 DONALD LANDRY,” WILLIAM J. MILLARD, THOMAS M. BADGER,* MICHAEL A. ARNOLD, AND JOSEPH B. MARTIN Department of Neurology and *Department of Gynecology, Massachusetts General Hospital, Boston, Massachusetts 02114 Received July 31, 1981; Accepted October 8, 1981 - Abstract Selective neurotoxins have been of value in providing a means for specifically interfering with the actions of endogenous neurotransmitter candidates. Others have shown cysteamine (CSH) to deplete the gastrointestinal tract and hypothalamus of rats of immunoreactive somatostatin, suggesting a toxic action of that compound directed against somatostatin-containing cells. The present study further defines the actions of cysteamine on somatostatin in the central nervous system (CNS). Cysteamine hydrochloride administered subcutaneously results in a depletion of somatostatin-like immunoreactivity (SLI) in the retina, brain, and cervical spinal cord of rats. The effect is demon- strable at doses of 30 mg/kg of body weight and above, occurs within 2 to 4 hr of a single injection of the drug, and is largely reversible within 1 week. The mean depletion of SLI observed within the CNS varies from 38% in cerebral cortex to 65% in cervical spinal cord 24 hr following administration of CSH, 300 mg/kg of body weight, S.C. By gel permeation chromatography, all molecular weight forms of SLI are affected, with the largest reductions in those forms that co-chromatograph with synthetic somatostatin-14 and somatostatin-28.
    [Show full text]
  • Regulatory Mechanisms of Somatostatin Expression
    International Journal of Molecular Sciences Review Regulatory Mechanisms of Somatostatin Expression Emmanuel Ampofo * , Lisa Nalbach, Michael D. Menger and Matthias W. Laschke Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany; [email protected] (L.N.); [email protected] (M.D.M.); [email protected] (M.W.L.) * Correspondence: [email protected]; Tel.: +49-6841-162-6561; Fax: +49-6841-162-6553 Received: 25 May 2020; Accepted: 9 June 2020; Published: 11 June 2020 Abstract: Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress growth hormone secretion and are involved in the regulation of glucagon and insulin synthesis in the pancreas. In recent years, the processing and secretion of somatostatin have been studied intensively. However, little attention has been paid to the regulatory mechanisms that control its expression. This review provides an up-to-date overview of these mechanisms. In particular, it focuses on the role of enhancers and silencers within the promoter region as well as on the binding of modulatory transcription factors to these elements. Moreover, it addresses extracellular factors, which trigger key signaling pathways, leading to an enhanced somatostatin expression in health and disease. Keywords: somatostatin; pre-prosomatostatin; δ-cells; central nervous system (CNS); gut; hypothalamus; cAMP resonse element (CRE); pancreas/duodenum homeobox protein (PDX)1; paired box protein (PAX)6; growth hormone (GH); brain-derived neurotrophic factor (BDNF); glutamateric system; pancreas 1.
    [Show full text]
  • Plasma Somatostatin and Cholecystokinin Levels in Preterm Infants and Their Mothers at Birth
    0031-399819513706-0771$03.0010 PEDIATRIC RESEARCH Vol. 37, No. 6, 1995 Copyright O 1995 International Pediatric Research Foundation, Inc Printed in U.S.A. Plasma Somatostatin and Cholecystokinin Levels in Preterm Infants and Their Mothers at Birth C.-J. TORNHAGE, F. SERENIUS, K. UVNAS-MOBERG,AND T. LINDBERG Department of Pediatrics, UmeB University, UmeB [C.-J.T., F.S., T.L.] and Department of Pharmacology, Karolinska Institute, Stockholm, Sweden [K. U-M.] Regulatory gut peptides play an important role in regulating same. They were also independent of sex, birth weight, gesta- the gastrointestinal tract. Our knowledge about the pattern of tional age, umbilical cord blood pH, or glucose level. In mothers, secretion and function of these peptides is scanty in preterm but not in infants, plasma SS levels were higher after vaginal infants. Therefore, plasma somatostatin (SS) and cholecystokinin delivery than after cesarean section. After multiple birth, new- (CCK) levels were estimated just after birth in 65 mothers and 73 born plasma SS, but not plasma CCK, was significantly lower preterm infants (umbilical cord blood). The gestational age was than after single birth (9.1 + 7.7 versus 16.9 2 12.7 pmol/L). 32 (24-36 median ranges) wk and birth weight 1900 (475-3350) (Pediatr Res 37: 771-776, 1995) g. The umbilical cord blood pH was 7.32 + 0.10 (mean t- SD). After Sep-Pak-C,, semichromatography of plasma, SS and CCK Abbreviations were analyzed by RIA. Both plasma SS and CCK levels were SS, somatostatin significantly higher in infants than in mothers (SS = 14.5 i.
    [Show full text]
  • 1 Advances in Therapeutic Peptides Targeting G Protein-Coupled
    Advances in therapeutic peptides targeting G protein-coupled receptors Anthony P. Davenport1Ϯ Conor C.G. Scully2Ϯ, Chris de Graaf2, Alastair J. H. Brown2 and Janet J. Maguire1 1Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, CB2 0QQ, UK 2Sosei Heptares, Granta Park, Cambridge, CB21 6DG, UK. Ϯ Contributed equally Correspondence to Anthony P. Davenport email: [email protected] Abstract Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) — nearly fifty GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first- in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, and both to introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to bias ligands to activate specific downstream signalling pathways in order to optimise efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma-half life have been revolutionary. Here, we discuss the current status of peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties. Introduction G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of drugs in clinical use1. Although most GPCR-targeting therapeutics are small molecules2, the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful.
    [Show full text]
  • Endocrine Regulation of Appetite and Growth in Atlantic Cod (Gadus Morhua)
    ENDOCRINE REGULATION OF APPETITE AND GROWTH IN ATLANTIC COD (GADUS MORHUA) by Meiyu Xu A thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Doctor of Science Department of Biology Faculty of Science Memorial University ofNewfoundland May, 2009 St. John' s Newfoundland Abstract Atlantic cod, Gadus morhua, is an important commercial fisheries species in many North Atlantic countries. Due to the recent decline in cod populations worldwide, Atlantic cod has become an emerging species in aquaculture in Canada, in particular New Brunswick, and Newfoundland and Labrador. The well-developed resistance to long-term starvation also makes cod a good model for the study of growth- and appetite-related hormones under both short-and long-term nutritional changes. The endocrinal regulation of food intake and energy homeostasis involves a two-way communication of hormones existing in central nervous system and several peripheral organs. I aimed to identify and characterizing genes coding for two growth-related factors (P ACAP and SS), as well as one central (OX) and two peripheral (ghrelin and GRP) appetite-related factors in Atlantic cod. Multiple alignments and phylogenetic analyses show that the amino acid sequences all 5 peptides appear relatively conserved among fish, at least among teleosts. The typical expression patterns reflect their functional regions and are highly similar to those of other teleosts reported so far, with high forebrain expression levels for brain peptides and high stomach expression levels for gut peptides. For all the peptides in the present study, an early appearance in development probably indicates a crucial role in development.
    [Show full text]
  • Evolution of Vertebrate Endocrine and Neuronal Gene Families
    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 856 Evolution of Vertebrate Endocrine and Neuronal Gene Families Focus on Pituitary and Retina DANIEL OCAMPO DAZA ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-8579-5 UPPSALA urn:nbn:se:uu:diva-191829 2013 Dissertation presented at Uppsala University to be publicly examined in B7:101a, Uppsala Biomedical Centre, BMC, Husargatan 3, Uppsala, Friday, March 1, 2013 at 09:00 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Abstract Ocampo Daza, D. 2013. Evolution of Vertebrate Endocrine and Neuronal Gene Families: Focus on Pituitary and Retina. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 856. 55 pp. Uppsala. ISBN 978-91-554-8579-5. The duplication of genes followed by selection is perhaps the most prominent way in which molecular biological systems gain multiplicity, diversity and functional complexity in evolution. Whole genome duplications (WGDs) therefore have the potential of generating an extraordinary amount of evolutionary innovation. It is now accepted that the vertebrate lineage has gone through two rounds of WGD in its early stages, after the divergence of invertebrate chordates and before the emergence of jawed vertebrates. These basal vertebrate WGDs are called 2R for two rounds of whole genome duplication. An additional WGD called 3R occurred early in the evolution of teleost fishes, before the radiation of this species-rich group. This thesis describes the evolution of several endocrine and neuronal gene families in relation to the vertebrate WGDs, through a comparative genomic approach including both phylogenetic analyses and chromosomal location data across a wide range of vertebrate taxa.
    [Show full text]
  • Pituitary Gland in Vitro: Evects of Somatostatin-14, Insulin-Like Growth Factor-I, and Nutritional Status
    General and Comparative Endocrinology 141 (2005) 93–100 www.elsevier.com/locate/ygcen Growth hormone secretion from the Arctic charr (Salvelinus alpinus) pituitary gland in vitro: eVects of somatostatin-14, insulin-like growth factor-I, and nutritional status C. Camerona,¤, R.D. Mocciab, J.F. Leatherlanda a Department of Biomedical Sciences, University of Guelph, Guelph, Ont., Canada N1G 2W1 b Department of Animal and Poultry Science, University of Guelph, Guelph, Ont., Canada N1G 2W1 Received 27 February 2004; revised 3 November 2004; accepted 29 November 2004 Available online 8 January 2005 Abstract This study investigated the inXuence of nutritional status on the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis in Arctic charr (Salvelinus alpinus). The objectives were to study the regulation of GH secretion in vitro by somatostatin-14 (SRIF) and hIGF-I, and to determine whether pituitary sensitivity to these factors is dependent upon nutritional status. Arctic charr were fed at three diVerent ration levels (0, 0.35, and 0.70% BW d¡1), and pituitary glands were harvested at 1, 2, and 5 weeks for in vitro study. Both SRIF and hIGF-I inhibited GH secretion from Arctic charr pituitary tissue in long-term (18 h) static hemipituitary cul- ture, as well as after acute exposure in a pituitary fragment perifusion system. This response appeared to be dose-dependent for SRIF in static culture over the range of 0.01–1 nM, but not for hIGF-I. The acute inhibitory action of hIGF-I on GH release in the perifusion system suggests an action that is initially independent of any eVects on GH gene expression or protein synthesis.
    [Show full text]
  • Pancreatic Somatostatin Expressing-Cells: an Untapped Source for Β-Cell Regeneration?
    Pancreatic somatostatin expressing-cells : an untapped source for β-cell regeneration ? Noemie Druelle To cite this version: Noemie Druelle. Pancreatic somatostatin expressing-cells : an untapped source for β-cell regener- ation ?. Agricultural sciences. Université Côte d’Azur, 2016. English. NNT : 2016AZUR4106. tel-01942168 HAL Id: tel-01942168 https://tel.archives-ouvertes.fr/tel-01942168 Submitted on 3 Dec 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE COTE D’AZUR – UFR SCIENCES Ecole Doctorale des Sciences de la Vie et de la Santé (ED85) THESE Pour l’obtention du titre de Docteur en Sciences de la Vie et de la Santé Spécialité : Recherche Clinique et Thérapeutique Présentée et soutenue par Noémie DRUELLE Pancreatic somatostatin expressing-cells: an untapped source for β-cell regeneration? Soutenue publiquement le 2 décembre 2016 devant le jury composé de : Prof. François Cuzin Président Dr. Miriam Cnop Rapporteur Dr. Jacob Hecksher-Sørensen Rapporteur Prof. Ahmed Mansouri Examinateur Dr. Patrick Collombat Directeur de thèse ACKNOWLEDGEMENTS Soyons reconnaissants aux personnes qui nous donnent du bonheur ; elles sont les charmants jardiniers par qui nos âmes sont fleuries. Marcel Proust Mes premiers remerciements s’adressent à mon directeur de thèse Patrick Collombat, sans qui ce joli projet n’aurait pas vu le jour.
    [Show full text]
  • Regulation of CRH-Induced Secretion of ACTH and Corticosterone By
    European Journal of Endocrinology (2005) 153 R7–R10 ISSN 0804-4643 RAPID COMMUNICATION Regulation of CRH-induced secretion of ACTH and corticosterone by SOM230 in rats A P Silva, P Schoeffter, G Weckbecker, C Bruns and H A Schmid Novartis Institutes for BioMedical Research, Basel, Switzerland (Correspondence should be addressed to H Schmid; Email: [email protected]) Abstract Objective: Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is biochemically characterized by increased plasma concentrations of ACTH inducing hypersecretion of cortisol. Somatostatin is known to inhibit ACTH secretion, and in vitro data have shown the inhibition of ACTH secretion by agonists activating sst2 and sst5 receptors. The present study aimed to determine the inhibitory effect of the multireceptor ligand SOM230, compared with the sst2-preferring agonist octreotide, on corticotropin-releasing hormone (CRH)-stimulated secretion of ACTH and corticoster- one in rats. Methods: Secretion of ACTH and corticosterone was induced by i.v. application of CRH (0.5 mg/kg) in rats pretreated 1 h before by i.v. application of SOM230 (1, 3, or 10 mg/kg), octreotide (10 mg/kg) or NaCl 0.9%. Results: SOM230 (3 and 10 mg/kg) inhibited CRH-induced ACTH release by 45^3% and 51^2%, respectively, and corticosterone release by 43^5% and 27^16%, respectively. 10 mg/kg of octreotide tended to be less potent at inhibiting ACTH release (34^6% inhibition) and did not alter the secretion of corticosterone. Conclusion: SOM230 has a stronger inhibitory effect on ACTH and corticosterone secretion than octreotide in rats. This difference can be explained by its higher affinity to sst1, sst3 and especially sst5 receptors compared with octreotide.
    [Show full text]
  • Inhibition of Gastrin Release by Secretin Is Mediated by Somatostatin in Cultured Rat Antral Mucosa
    Inhibition of gastrin release by secretin is mediated by somatostatin in cultured rat antral mucosa. M M Wolfe, … , G M Reel, J E McGuigan J Clin Invest. 1983;72(5):1586-1593. https://doi.org/10.1172/JCI111117. Research Article Somatostatin-containing cells have been shown to be in close anatomic proximity to gastrin-producing cells in rat antral mucosa. The present studies were directed to examine the effect of secretin on carbachol-stimulated gastrin release and to assess the potential role of somatostatin in mediating this effect. Rat antral mucosa was cultured at 37 degrees C in Krebs-Henseleit buffer, pH 7.4, gassed with 95% O2-5% CO2. After 1 h the culture medium was decanted and mucosal gastrin and somatostatin were extracted. Carbachol (2.5 X 10(-6) M) in the culture medium increased gastrin level in the medium from 14.1 +/- 2.5 to 26.9 +/- 3.0 ng/mg tissue protein (P less than 0.02), and decreased somatostatin-like immunoreactivity in the medium from 1.91 +/- 0.28 to 0.62 +/- 0.12 ng/mg (P less than 0.01) and extracted mucosal somatostatin-like immunoreactivity from 2.60 +/- 0.30 to 1.52 +/- 0.16 ng/mg (P less than 0.001). Rat antral mucosa was then cultured in the presence of secretin to determine its effect on carbachol-stimulated gastrin release. Inclusion of secretin (10(-9)-10(-7) M) inhibited significantly carbachol-stimulated gastrin release into the medium, decreasing gastrin from 26.9 +/- 3.0 to 13.6 +/- 3.2 ng/mg (10(-9) M secretin) (P less than 0.05), to 11.9 +/- 1.7 ng/mg (10(-8) secretin) (P less than 0.02), and to 10.8 +/- 4.0 ng/mg (10(-7) M secretin) (P less than […] Find the latest version: https://jci.me/111117/pdf Inhibition of Gastrin Release by Secretin Is Mediated by Somatostatin in Cultured Rat Antral Mucosa M.
    [Show full text]
  • The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep
    Graduate Theses, Dissertations, and Problem Reports 2017 The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep Richard B. McCosh Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation McCosh, Richard B., "The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep" (2017). Graduate Theses, Dissertations, and Problem Reports. 6194. https://researchrepository.wvu.edu/etd/6194 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep Richard B. McCosh Dissertation submitted to the School of Medicine at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Biomedical Science Cellular and Integrative Physiology Robert L. Goodman, PhD; Mentor Stanley M. Hileman, PhD; Chair Michael W. Vernon, PhD Steven L. Hardy, PhD Donal C. Skinner, PhD Department of Physiology and Pharmacology Morgantown, West Virginia 2017 Key Words: gonadotropin releasing hormone, luteinizing hormone, somatostatin, kisspeptin, sheep Copyright 2017 Richard B.
    [Show full text]