GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENALEfficacy of Ipamorelin, a Novel Ghrelin Mimetic, in a Rodent Model of Postoperative Ileus
ABSTRACT
Ghrelin and ghrelin mimetics stimulate appetite and enhance gastric motility. The present study investigates whether ipamorelin, a selective growth hormone secretagogue and agonist of the ghrelin receptor, would accelerate gastrointestinal transit and ameliorate the symptoms in a rodent model of postoperative ileus (POI). Fasted male rats were subjected to laparotomy and intestinal manipulation. At the end of surgery, a dye marker was infused in the proximal colon to evaluate postsurgical colonic transit time, which was the time to the first bowel movement. In addition, fecal pellet output, food intake, and body weight were monitored regularly for 48 h. Ipamorelin (0.01–1 mg/kg), growth hormone-releasing peptide (GHRP)-6 (20 μg/kg), or vehicle (saline) were administered via intravenous bolus infusion after a single dosing or a 2-day repetitive dosing regimen (four doses a day at 3-h intervals). Compared with the vehicle, a single dose of ipamorelin (1 mg/kg) or GHRP-6 (20 μg/kg) decreased the time to the first bowel movement but had no effect on cumulative fecal output, food intake, or body weight gain measured 48 h after the surgery. In contrast, repetitive dosing of ipamorelin (0.1 or 1 mg/kg) significantly increased the cumulative fecal pellet output, food intake, and body weight gain. The results suggest that postsurgical intravenous infusions of ipamorelin may ameliorate the symptoms in patients with POI.
Access through your organization
Check access to the full text by signing in through your organization.Access through your organization
Section snippets
Materials and Methods
Animals. Adult male Sprague-Dawley rats were obtained from Charles River Laboratories, Inc. (Wilmington, MA) at an initial body weight of 250 to 270 g. An acclimation period of at least 1 week was allowed before the experiments. All rats were single-housed with free access to food and water at 21 to 23°C and a 12-h light/dark cycle. The animals were purchased with indwelling catheters implanted in the right jugular vein for administration of drugs or vehicle. The catheters were maintained
Results
The Rat Model of POI. To study the effect of surgery on GI function, we evaluated surgery-induced inhibition of the propulsive motility of the colon by measuring the colonic transit time to the first bowel movement after surgery and the cumulative fecal output for 48 h. Food intake and body weight were also measured. In the present study, abdominal surgery was found to delay colonic transit, causing a significant increase of the time to the first bowel movement registered by the appearance of a
Discussion
The rat model of POI induced by manipulation of the bowel is commonly used to investigate the pathogenic mechanisms relevant to the postsurgical development of GI dysfunction in humans and to investigate the efficacy of new therapeutic treatments. In previous studies, rats with POI showed a significant delay in colonic transit times and a decrease in fecal pellet output and food intake compared with control animals (Fraser et al., 2009). Data presented in this study confirm that colonic
Acknowledgments
We thank Kristen Campbell-Dittmeyer for excellent technical assistance.
References (42)
Ahnfelt-Rønne I, Nowak J, and Olsen UB (2001) Do growth hormone-releasing peptides act as ghrelin secretagogues?... Ariga H, Tsukamoto K, Chen C, Mantyh C, Pappas TN, and Takahashi T (2007) Endogenous acyl ghrelin is involved in... Banks WA, Tschöp M, Robinson SM, and Heiman ML (2002) Extent and direction of ghrelin transport across the blood-brain... Bassil AK, Dass NB, and Sanger GJ (2006) The prokinetic-like activity of ghrelin in rat isolated stomach is mediated... Bauer AJ and Boeckxstaens GE (2004) Mechanisms of postoperative ileus. Neurogastroenterol Motil 16:... Condon RE, Frantzides CT, Cowles VE, Mahoney JL, Schulte WJ, and Sarna SK (1986) Resolution of postoperative ileus in... Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, et... Dass NB, Munonyara M, Bassil AK, Hervieu GJ, Osbourne S, Corcoran S, Morgan M, and Sanger GJ (2003) Growth hormone... Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, and Nakazato M (2002) The role of the... Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, Spedding M, Kojima M, and Kangawa K (2005)...
de Jonge WJ, van den Wijngaard RM, The FO, ter Beek ML, Bennink RJ, Tytgat GN, Buijs RM, Reitsma PH, van Deventer SJ,... De Winter BY, De Man JG, Seerden TC, Depoortere I, Herman AG, Peeters TL, and Pelckmans PA (2004) Effect of ghrelin and... Edholm T, Levin F, Hellström PM, and Schmidt PT (2004) Ghrelin stimulates motility in the small intestine of rats... Fraser GL, Venkova K, Hoveyda HR, Thomas H, and Greenwood-Van Meerveld B (2009) Effect of the ghrelin receptor agonist... Fujino K, Inui A, Asakawa A, Kihara N, Fujimura M, and Fujimiya M (2003) Ghrelin induces fasted motor activity of the... Gobburu JV, Agersø H, Jusko WJ, and Ynddal L (1999) Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth... Greenwood-Van Meerveld B (2007) Emerging drugs for postoperative ileus. Expert Opin Emerg Drugs 12:... Hoveyda H, Peterson M, Fraser G, and Ramaseshan M (2006), inventors; Tranzyme Pharma, Inc., assignee. Macrocyclic... Inui A (2001) Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2:... Jiménez-Reina L, Cañete R, de la Torre MJ, and Bernal G (2002) Influence of chronic treatment with the growth hormone... Kalff JC, Schraut WH, Simmons RL, and Bauer AJ (1998) Surgical manipulation of the gut elicits an intestinal muscularis...
This work was supported by Sapphire Therapeutics, Inc.
doi:10.1124/jpet.108.149211.
ABBREVIATIONS: POI, postoperative ileus; GI, gastrointestinal; GRLN, ghrelin; GHRP, growth hormone-releasing peptide; ANOVA, analysis of variance; TZP-101, (4R,7S,10R,13R)-7-cyclopropyl-13-(4-fluorobenzyl)-3-oxa-6,9,12,15-tetraaza-4,9,10-trimethyl-4,5,6,7,10,12,13,15,16,17,18-undecahydro-1,2-benzocyclooctadecene-8,11,14-trione; GSK894281, N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluoro-4-(5-methyl-2-furanyl) benzenesulphonamide.View full text
U.S. Government work not protected by U.S. copyright