GASTRIC MOTILITY

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

T Kitazawa^*, B De Smet, K Verbeke, I Depoortere, T L Peeters

Centre for Gastroenterological Research, Catholic University of Leuven, Leuven, Belgium

Correspondence to:
Professor I Depoortere
Centre for Gastroenterological Research, Gasthuisberg O&N, box 701, B-3000 Leuven, Belgium; inge.depoortere{at}med.kuleuven.be

Background and aims: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare the effect of ghrelin with that of synthetic peptide (growth hormone releasing peptide 6 (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, N^G-nitro-L-arginine methyl ester hydrochloride (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 stimulation (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 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.

Abbreviations: GH, growth hormone; GHS, growth hormone secretagogue; GHS-R, growth hormone secretagogue receptor; GHRP-6, growth hormone releasing peptide 6; L-NAME, N^G-nitro-L-arginine methyl ester hydrochloride; EFS, electrical field stimulation

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

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