Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus.
Ghrelin, the natural ligand of the growth hormone secretagogue receptor (ghrelin receptor), is an orexigenic gut hormone with prokinetic action in the upper gastrointestinal tract. Previously we have shown in a rodent model of postoperative ileus that the synthetic ghrelin receptor agonist TZP-101 prevents the delay in gastric emptying and improves small intestinal transit. The goal of the present study was to investigate whether TZP-101 affects colonic transit and food intake in rats with postoperative ileus. Fasted rats were treated with morphine and subjected to laparotomy under isoflurane anesthesia. Following surgery the animals were placed in clean home cages and fecal pellet output and food intake were monitored for 48 h. TZP-101 or vehicle were administered as 3 i.v. bolus infusions at 0 h, 2 h and 4 h post-surgery. TZP-101 (0.03-1 mg/kg) dose-dependently decreased the time to first bowel movement and increased fecal pellet output measured at 12 h and 24 h post-surgery compared to the vehicle. The administration of TZP-101 was not associated with a significant alteration in food intake. In conclusion, this study provides the first experimental evidence that a novel ghrelin receptor agonist improves large bowel function in rats with postoperative ileus, suggesting that TZP-101 may be useful in the clinic to accelerate upper gastrointestinal transit and to shorten the time to the first bowel movement following surgery.
Fraser
Graeme L
GL
Tranzyme Pharma, Sherbrooke, QC, Canada, J1H 5N4.
Venkova
Kalina
K
Hoveyda
Hamid R
HR
Thomas
Helmut
H
Greenwood-Van Meerveld
Beverley
B
D000005:Abdomen / Q000601:surgery; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000378:metabolism / Q000503:physiopathology*; D003672:Defecation / Q000187:drug effects; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects*; D045823:Ileus / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D047028:Macrocyclic Compounds / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000627:therapeutic use; D011183:Postoperative Complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists*; D013997:Time Factors
D047028:Macrocyclic Compounds; D054440:Receptors, Ghrelin; D009020:Morphine; C528884:ulimorelin