Top

Published in:

01-09-2007 | Original Paper

Prokinetic Effects of a New Ghrelin Receptor Agonist TZP-101 in a Rat Model of Postoperative Ileus

Authors: Kalina Venkova, Graeme Fraser, Hamid R. Hoveyda, Beverley Greenwood-Van Meerveld

Published in: Digestive Diseases and Sciences | Issue 9/2007

Abstract

Postoperative ileus (POI) is a major cause of postoperative complications and prolonged hospitalization. Ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, has been found to stimulate gastric motility and accelerate gastric emptying. The present study investigates whether TZP-101 (0.03–1 mg/kg i.v.), a synthetic ghrelin-receptor agonist, could improve gastrointestinal transit in rats with POI. Since the main factors for the development of POI are the surgical manipulation and the gastrointestinal effects of opioid-receptor agonists used for pain management, the effect of TZP-101 was investigated in rats subjected to surgery, to morphine treatment (3 mg/kg s.c.), or to a combination of both. The results showed that TZP-101 is equally effective against the delayed gastrointestinal transit induced by surgery, by morphine, or by the combination of both interventions. The prokinetic action of TZP-101 was more pronounced in the stomach compared to the small intestine.

Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660PubMedCrossRef

Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K (2000) Ghrelin strongly stimulates growth hormone (GH) release in humans. J Clin Endocinol Metab 85:4909–4911

Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatli MA, Bloom SR (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992PubMedCrossRef

Peeters TL (2006) Ghrelin: a new player in the control of gastrointestinal functions. Gut 54:1638–1649CrossRef

Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141:4255–4261PubMedCrossRef

Kojima M, Kangawa K (2005) Ghrelin: structure and function. Physiol Rev 85:495–522PubMedCrossRef

Dass NB, Munonyara M, Bassil AK, Hervieu GJ, Osbourne S, Corcoran S, Morgan M, Sanger GJ (2003) Growth hormone secretagogue receptors in rat and human gastrointestinal tract and the effects of ghrelin. Neuroscience 120:443–453PubMedCrossRef

Xu L, Depoortere I, Tomasetto C, Zandecki M, Tang M, Timmermans JP, Peeters TL (2005) Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus. Regul Pept 124:119–125PubMedCrossRef

Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M (2001) Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterol 120:337–345CrossRef

10.

Fukuda H, Mizuta Y, Isomoto H, Takeshima F, Ohnita K, Ohba K, Omagari K, Taniyama K, Kohno S (2004) Ghrelin enhances gastric motility through direct stimulation of intrinsic neural pathways and capsaicin-sensitive afferent neurones in rats. Scand J Gastroenterol 39:1209–1214PubMedCrossRef

11.

Tebbe JJ, Tebbe CG, Mronga S, Ritter M, Schafer MK (2005) Central neuropeptide Y receptors are involved in 3rd ventricular ghrelin induced alteration of colonic transit time in conscious fed rats. BMC Gastroenterol 5:5PubMedCrossRef

12.

Shimizu Y, Chang EC, Shafton AD, Ferens DM, Sanger GJ, Witherington J, Furness JB (2006) Evidence that stimulation of ghrelin receptors in the spinal cord initiates propulsive activity in the colon of the rat. J Physiol 576:329–338

13.

Trudel L, Tomasetto C, Rio MC, Bouin M, Plourde V, Eberling P, Poitras P (2002) Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat. Am J Physiol Gastrointest Liver Physiol 282:G948–G952PubMed

14.

De Winter BY, De Man JG, Seerden TC, Depoortere I, Herman AG, Peeters TL, Pelckmans PA (2004) Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice. Neurogastroenterol Motil 16:439–446PubMedCrossRef

15.

Liu YL, Malik NM, Sanger GJ, Andrews PLR (2006) Ghrelin alleviates cancer chemotherapy-associated dyspepsia in rodents. Cancer Chemother Pharmacol 58:326–333PubMedCrossRef

16.

Levin F, Edholm T, Schmidt PT, Grybäck P, Jacobsson H, Degerblad M, Höybye C, Holst JJ, Rehfeld JF, Hellström PM, Näslund E (2006) Ghrelin stimulates gastric emptying and hunger in normal weight humans. J Clin Endocrin Metab 91:3296–3302

17.

Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T (2005) Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Aliment Pharmacol Ther 22:847–853PubMedCrossRef

18.

Murray CD, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, Johnston C, Bloom SR, Emmanuel AV (2005) Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 54:1693–1698PubMedCrossRef

19.

Binn M, Albert C, Gougeon A, Maerki H, Coulie B, Lemoyne M, Rabasa Lhoret R, Tomasetto C, Poitras P (2006) Ghrelin gastrokinetic action in patients with neurogenic gastroparesis. Peptides 27:1603–1606PubMedCrossRef

20.

Kehlet H, Williamson R, Buchler MW, Beart RW (2005) A survey of perceptions and attitudes among European surgeons towards the clinical impact and management of postoperative ileus. Colorectal Dis 7:245–250PubMedCrossRef

21.

Fotiadis RJ, Badvie S, Westen MD, Allen-Mersh TG (2004) Epidural analgesia in gastrointestinal surgery. Br J Surg 91:828–841PubMedCrossRef

22.

Greenwood-Van Meerveld B, Gardner CJ, Little PJ, Hicks GA, Dehaven-Hudkins DL (2004) Preclinical studies of opioids and opioid antagonists on gastrointestinal function. Neurogastroenterol Motil 16:46–53PubMedCrossRef

23.

Wittbrodt E (2006) The impact of postoperative ileus and emerging therapies. P&T 31:39–59

24.

Fraser GL, Hoveyda HR, Venkova K, Johnson A, Samia M, Greenwood-Van Meerveld B, Tannenbaum GS (2005) Pharmacological separation of gastrointestinal and endocrine effects of ghrelin using a novel ghrelin agonist, TZP-101. Neurogastroenterol Motil 17:85

25.

Kälff JC, Schraut WH, Simmons RL, Bauer AJ (1998) Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann Surg 228:652–663PubMedCrossRef

26.

Miller MS, Galligan JJ, Burks TF (1981) Accurate measurement of intestinal transit in the rat. J Pharmacol Methods 6:211–217PubMedCrossRef

27.

Crooks PA, Kottayil SG, Al-Ghananeem AM, Byrn SR, Butterfield DA (2006) Opiate receptor binding properties of morphine-, dihydromorphine-, and codeine 6-O-sulfate ester congeners. Bioorg Med Chem Lett 16:4291–4295PubMedCrossRef

28.

Poitras P, Polvino WJ, Rocheleau B (2005) Gastrokinetic effect of ghrelin analog RC-1139 in the rat. Effect on post-operative and on morphine induced ileus. Peptides 26:1598–1601PubMedCrossRef

29.

De Winter BY, Boeckxstaens GE, De Man JG, Moreels TG, Herman AG, Pelckmans PA (1997) Effect of adrenergic and nitrergic blockade on experimental ileus in rats. Br J Pharmacol 120:464–468PubMedCrossRef

30.

Espat NJ, Cheng G, Kelley MC, Vogel SB, Sninsky CA Hocking MP (1995) Vasoactive intestinal peptide and substance P receptor antagonists improve postoperative ileus. J Surg Res 58:719–723PubMedCrossRef

31.

Kälff JC, Türler A, Schwarz NT, Schraut WH, Lee KK, Tweardy DJ, Billiar TR, Simmons RL, Bauer AJ (2003) Intra-abdominal activation of a local inflammatory response within the human muscularis externa during laparotomy. Ann Surg 237:301–315PubMedCrossRef

32.

Schwarz NT, Beer-Stolz D, Simmons RL, Bauer AJ (2002) Pathogenesis of paralytic ileus: intestinal manipulation opens a transient pathway between the intestinal lumen and the leukocytic infiltrate of the jejunal muscularis. Ann Surg 235:31–40PubMedCrossRef

33.

De Jonge WJ, The FO, Van Der Zanden EP, Van Den Wijngaard RM, Boeckxstaens GE (2005) Inflammation and gut motility; neural control of intestinal immune cell activation. J Pediatr Gastroenterol Nutr 41:S10–S11PubMedCrossRef

34.

Konturek PC, Brzozowski T, Pajdo R, Nikiforuk A, Kwiecien S, Harsch I, Drozdowicz D, Hahn EG, Konturek SJ (2004) Ghrelin—a new gastroprotective factor in gastric mucosa. J Physiol Pharmacol 55:325–336PubMed

35.

Bassil AK, Dass NB, Murray CD, Muir A, Sanger GJ (2005) Prokineticin-2, motilin, ghrelin and metoclopramide: prokinetic utility in mouse stomach and colon. Eur J Pharmacol 524:138–144PubMedCrossRef

36.

Kitazawa T, De Smet B, Verbeke K, Depoortere I, Peeters TL (2005) Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro. Gut 54:1078–1084PubMedCrossRef

37.

38.

Fujino K, Inui A, Asakawa A, Kihara N, Fujimura M, Fujimiya M (2003) Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J Physiol 550:227–240PubMedCrossRef

39.

Bassil AK, Dass NB, Sanger GJ (2006) The prokinetic-like activity of ghrelin in rat isolated stomach is mediated via cholinergic and tachykinergic motor neurones. Eur J Pharmacol 544:146–152PubMedCrossRef

40.

Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123:1120–1128PubMedCrossRef

41.

Sakata I, Yamazaki M, Inoue K, Hayashi Y, Kangawa K, Sakai T (2003) Growth hormone secretagogue receptor expression in the cells of the stomach-projected afferent nerve in the rat nodose ganglion. Neurosci Lett 342:183–186PubMedCrossRef

42.

Edholm T, Levin F, Hellstrom PM, Schmidt PT (2004) Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regul Pept 121:25–30PubMedCrossRef

43.

Artinyan A, Nunoo-Mensah JW, Essani R, Balasubramaniam S, Gauderman J, Gonzalez-Ruiz C, Vukasin P, Kaiser AM, Beart RW (2005) Prolonged postoperative ileus: definition, risk factors and predictors in patients undergoing open colorectal surgery. Gastroenterology 128:A-979

44.

Senagore AJ (2006) Overview of POI and its impact on surgical outcomes. Supplement Contemp Surg (March 2006) 4–7

45.

Galligan JJ, Burks TF (1983) Centrally mediated inhibition of small intestinal transit and motility by morphine in the rat. J Pharmacol Exp Ther 226:356–361PubMed

46.

Gmerek DE, Cowan A, Woods JH (1986) Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats. J Pharmacol Exp Ther 236:8–13PubMed

47.

Thorn SE, Wickbom G, Philipson L, Leissner P, Wattwil M (1996) Myoelectric activity in the stomach and duodenum after epidural administration of morphine or bupivacaine. Acta Anaesthesiol Scand 40:773–778PubMedCrossRef

48.

Schmidt WK (2001) Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg 182:27S–38SPubMedCrossRef

49.

Murphy DB, Sutton JA, Prescott LF, Murphy MB (1997) Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 87:765–770PubMedCrossRef

50.

Fukuda H, Suenaga K, Uemura K, Tsuchida D, Mantyh CR, Papas TN, Hicks GA, Takahashi T (2004) The selective mu opioid receptor antagonist, alvimopan, accelerates gastrointestinal transit in a rodent model of postoperative ileus. Gastroenterol 126:A-641

Title: Prokinetic Effects of a New Ghrelin Receptor Agonist TZP-101 in a Rat Model of Postoperative Ileus
Authors: Kalina Venkova
Graeme Fraser
Hamid R. Hoveyda
Beverley Greenwood-Van Meerveld
Publication date: 01-09-2007
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 9/2007
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-007-9783-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 9/2007

Development of Specific Antibodies to an ARF Protein in Treated Patients with Chronic HCV Infection

Surgical Clip Migration and Choledocholithiasis: A Late, Abrupt Complication of Laparoscopic Cholecystectomy

Levels of Hepatitis B Virus (HBV) Replication During the Nonreplicative Phase: HBV Quantification by Real-Time PCR in Korea

Posttraumatic Growth, Immunity and Survival in Patients with Hepatoma

Helicobacter pylori May Play a Contributory Role in the Pathogenesis of Primary Sclerosing Cholangitis

Letter to the Editor

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials