Oxyntomodulin and its (19-37) and (30-37) fragments inhibit histamine-stimulated gastric acid secretion in the conscious rat.
Oxyntomodulin, a hormone released from jejuno-ileum and composed of the glucagon sequence extended by a C-terminal octapeptide displays original tissue specificity for the gastric mucosa. The aim of this study was to compare the effect of oxyntomodulin on histamine (0.4 mg/kg per h)-stimulated gastric acid secretion in the conscious rat to that of three of its fragments: oxyntomodulin-(19-37) produced from oxyntomodulin by enzymatic cleavage, oxyntomodulin-(30-37) corresponding to the molecular difference between oxyntomodulin and glucagon and oxyntomodulin-(32-37) produced during proglucagon processing to glucagon. The metabolic clearance rate (MCR) in the anesthetized rat was evaluated for each peptide. Oxyntomodulin, oxyntomodulin-(19-37) and oxyntomodulin-(30-37) inhibited the histamine-stimulated gastric acid secretion dose dependently. The dose-response curves for oxyntomodulin and oxyntomodulin-(19-37) were parallel. The potency of oxyntomodulin (19-37) (ED50 approximately 70 pmol/kg) was the same as that of oxyntomodulin (ED50 approximately 35 nmol/kg) after correction of the curve for the MCR (two-fold higher for the fragment). Although the dose-response curve for oxyntomodulin-(30-37) was not entirely parallel to that of the two other peptides, its maximal inhibition (at 15 nmol/kg) was the same as that of oxyntomodulin-(19-37). Thus, oxyntomodulin-(30-37) was an efficient as the longer molecules but approximately 150-fold less potent than oxyntomodulin. The MCR for oxyntomodulin-(30-37) was approximately 250 fold higher than that of oxyntomodulin, partly explaining the difference in potency. The (32-37) fragment, which is naturally released from the endocrine pancreas, was devoid of activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Carles-Bonnet
C
C
Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Montpellier, France.
Jarrousse
C
C
Niel
H
H
Martinez
J
J
Bataille
D
D
D000818:Animals; D003243:Consciousness; D005744:Gastric Acid / Q000378:metabolism*; D005747:Gastric Fistula; D004763:Glucagon-Like Peptides / Q000378:metabolism / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology*; D008297:Male; D053772:Oxyntomodulin; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D013997:Time Factors
D053772:Oxyntomodulin; D010446:Peptide Fragments; D004763:Glucagon-Like Peptides; D006632:Histamine