Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro

Takio Kitazawa ¹, Betty De Smet ², Kristin Verbeke ², Inge Depoortere ^2* and Theo Peeters ²

¹ Rakuno Gakuen University, Japan
² University of Leuven, Belgium

^* To whom correspondence should be addressed. E-mail: inge.depoortere{at}med.kuleuven.ac.be.

Accepted 8 April 2005

Abstract

Aims: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare ghrelin's effect with that of synthetic peptide (GHRP-6) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro.

Methods: In vivo, the dose-dependent effects (1- 150 nmol/kg) of ghrelin, GHRP-6 and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, L-NAME or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated. In vitro, the effect of the GHS-R agonists (1 µM) on electrical field (EFS) induced responses was studied in fundic strips in the absence and presence of L- NAME.

Results: Ghrelin, GHRP-6 and capromorelin accelerated gastric emptying in an equipotent manner with bell-shaped dose-response relationships. In the presence of atropine or L-NAME, which delayed gastric emptying, capromorelin failed to accelerate gastric emptying. D- Lys3-GHRP-6 also delayed gastric emptying but did not effectively block the action of the GHS-R agonists, but this may be related to interactions with other receptors. EFS of fundic strips caused frequency-dependent relaxations that were not modified by the GHS-R agonists. L-NAME turned the EFS-induced relaxations into cholinergic contractions that were enhanced by ghrelin, GHRP-6 and capromorelin.

Conclusion: The 14C octanoic breath test is a valuable technique to evaluate drug-induced effects on gastric emptying in mice. Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves.

Keywords: breath test, electrical field stimulation, gastric emptying, ghrelin, organ bath

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