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)
Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale de Pharmacologie-Endocrinologie, Montpellier, France.
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Jarrousse
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Carles-Bonnet
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Niel
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Sabatier
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Audousset-Puech
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Blache
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Kervran
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Martinez
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Bataille
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