Inhibition of gastric acid secretion by oxyntomodulin and its 19-37 fragment in the conscious rat.
Oxyntomodulin (Oxm) is a hormone, released from the intestine during digestion. Its target tissue is the gastric mucosa, where it inhibits acid secretion. It contains the 29-amino acid glucagon moiety, extended at its COOH-terminal end by an octapeptide. The glucagon moiety contains a basic doublet (Arg17-Arg18). Our working hypothesis was that the mode of action of Oxm may imply a processing of the molecule at the Arg-Arg doublet, releasing Oxm-(19-37). We compared the effect of Oxm with that of Oxm-(19-37) on gastric acid secretion in the conscious rat provided with a chronic gastric fistula. The acid secretion was plateau stimulated by a perfusion of either pentagastrin or histamine. Whereas Oxm or Oxm-(19-37) had no effect on basal acid secretion, both peptides inhibited pentagastrin (0.5 micrograms.kg-1.h-1)- and histamine (0.4 mg.kg-1.h-1)-stimulated acid secretion in a dose-dependent manner. When the metabolic clearance rate for each peptide was taken into account, the 19-37 fragment was as potent as the whole Oxm, regardless of the type of stimulant. When the dose of pentagastrin was increased from 0.175 to 1.1 micrograms.kg-1.h-1, the extent of inhibition induced by Oxm (40 pmol/kg) also increased. In contrast, when the dose of histamine was increased from 0.25 to 1.2 mg.kg-1.h-1, the extent of inhibition induced by Oxm (40 pmol/kg) decreased. Oxm-(19-37) (70-140 pmol/kg) displayed the same behavior as the whole molecule under both types of stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Jarrousse
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C
Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale de Pharmacologie-Endocrinologie, Montpellier, France.
Carles-Bonnet
C
C
Niel
H
H
Sabatier
R
R
Audousset-Puech
M P
MP
Blache
P
P
Kervran
A
A
Martinez
J
J
Bataille
D
D
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects; D004763:Glucagon-Like Peptides / Q000378:metabolism / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D053772:Oxyntomodulin; D010418:Pentagastrin / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D053772:Oxyntomodulin; D010446:Peptide Fragments; C081298:oxyntomodulin (19-37); D004763:Glucagon-Like Peptides; D006632:Histamine; D010418:Pentagastrin