Two new peptides to improve post-operative gastric ileus in dog

doi:10.1016/S0196-9781(03)00113-X

Peptides

Volume 24, Issue 4, April 2003, Pages 531-534

https://doi.org/10.1016/S0196-9781(03)00113-X Get rights and content

Abstract

Peptides can influence gastrointestinal motility, and from data obtained earlier in rats, we hypothesized that MTL-RP/Ghrelin, as well as CGRP receptor antagonist 8–37, could improve gastric post-operative ileus in dog. Dogs submitted to laparotomy were perfused with or saline or CGRP 8–37 or MTL-RP/Ghrelin on days 1–4 post-operatively while gastric emptying was estimated by measuring the postprandial increase in plasma acetaminophen ingested with a meal. As expected, in saline-treated animals the gastric emptying function was impaired post-operatively. The total amount of acetaminophen emptied (AUC over 150 min) on post-operative days 1–4 reached respectively 31±5%, 65±8%, 60±8% and 62±8% of the normal emptying capacity. CGRP antagonist increased the total emptying of acetaminophen to 52±5% on day 1, 95±2% on day 2 and 103±3% (P<0.05) on day 3. The delayed emptying of acetaminophen seen post-operatively in saline-treated animals could be completely reversed by MTL-RP/Ghrelin (P<0.01) whether it was given at 100 μg/kg on day 2 (102±7% of the normal emptying capacity), 4 μg/kg on day 3 (106±7%) or 20 μg/kg on day 4 (132±8%). As found earlier in rodents, CGRP receptor antagonist 8–37 as well as MTL-RP/Ghrelin are potent prokinetics to improve post-operative gastric ileus in dog.

Introduction

Peptides can influence gastrointestinal motility (for review, see [4]). Some peptides are already used as therapeutic agents; octreotide for example is useful to stimulate intestinal motility in some patients with intestinal pseudo obstruction [11] or as a palliation for intestinal obstruction in patients with malignant pre-terminal conditions [6].

Post-operative ileus is characterized by an impaired gastrointestinal motility in the early days following laparatomy. Post-operative ileus is a major factor delaying the recovery of patients following abdominal surgery. In some patients, this situation can be unfortunately prolonged and deleterious to the clinical recovery. The cause of post-operative ileus remains unclear [9], [10]; no specific treatment is recognized, but peptides could probably be useful [3].

From previous studies, we knew that two peptide products, MTL-RP/Ghrelin as well as CGRP receptor antagonist CGRP 8–37, were able to improve post-operative ileus in rat [8], [13]. The aim of this study was to verify if the stimulatory effect of the two peptide compounds on gastric motility during the early post-operative period can also be obtained in mammalian non-rodent animals. We therefore tested the effect of MTL-RP/Ghrelin or CGRP antagonist 8–37 on the gastric emptying function of the dog in the early days following laparatomy.

Section snippets

Methods

These studies were approved by the Animal Ethical Board of our institution. Female mongrel dogs (18–25 kg) were used for these studies.

Saline control condition

Five dogs were tested in these conditions. As expected, the gastric emptying function decreased post-operatively. The total amount of acetaminophen emptied (AUC over 150 min) on post-operative days 1–4 reached respectively 31±5, 65±8, 60±8 and 62±8% of the normal emptying capacity.

CGRP 8–37

Three dogs completed these studies. CGRP antagonist increased the total emptying of acetaminophen from 31±5% in saline-treated animals to 52±5% on day 1, from 65±8% to 95±2% on day 2 and from 60±8% to 103±3% (P<0.05)

Discussion

Our data therefore confirm the observation we made earlier in rats [8], [13] that the two peptide products we tested, MTL-RP/Ghrelin or CGRP antagonist 8–37, can improve the delay in gastric emptying observed after abdominal surgery.

MTL-RP/Ghrelin and CGRP are both expressed in human and although their effects on the human GI tract are not yet fully characterized, both are known to be bioactive in this species [2], [7], [12]. Our results are important since the documentation of the gastric

References (13)

A. Asakawa et al.
Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin
Gastroenterology
(2001)
C. Beglinger et al.
Distinct hemodynamic and gastric effects of human CGRP I and II in man
Peptides
(1991)
M. Fujimiya et al.
Peptidergic regulation of gastrointestinal motility in rodents
Peptides
(2000)
M.C. L’Heureux et al.
Digestive motor effects and vascular actions of CGRP in dog are expressed by different receptor subtypes
Peptides
(2000)
G. Mangili et al.
Octreotide in the management of bowel obstruction in terminal ovarian cancer
Gynecol. Oncol.
(1996)
V. Plourde et al.
CGRP antagonists and capsaicin on celiac ganglia partly prevent postoperative gastric ileus
Peptides
(1993)

There are more references available in the full text version of this article.

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Two new peptides to improve post-operative gastric ileus in dog

Abstract

Introduction

Section snippets

Methods

Saline control condition

CGRP 8–37

Discussion

Gastroenterology

Peptides

Peptides

Peptides

Gynecol. Oncol.

Peptides