Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro.
OBJECTIVE
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 microM) 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.


CONCLUSIONS
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.
Kitazawa
T
T
Centre for Gastroenterological Research, Catholic University of Leuven, Gasthuisberg O&N, box 701, B-3000 Leuven, Belgium.
De Smet
B
B
Verbeke
K
K
Depoortere
I
I
Peeters
T L
TL
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D018723:Bethanechol / Q000494:pharmacology; D001944:Breath Tests; D018678:Cholinergic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects; D054439:Ghrelin; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D036361:Peptide Hormones / Q000819:agonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects*
C433143:CP 424391; D018678:Cholinergic Agents; D004791:Enzyme Inhibitors; D054439:Ghrelin; D009842:Oligopeptides; D036361:Peptide Hormones; D010880:Piperidines; D011720:Pyrazoles; D018723:Bethanechol; C041048:growth hormone releasing hexapeptide; D001285:Atropine; D013007:Growth Hormone-Releasing Hormone; D019331:NG-Nitroarginine Methyl Ester