Oxyntomodulin and its (19-37) and (30-37) fragments inhibit histamine-stimulated gastric acid secretion in the conscious rat.

Abstract 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)-stimulatcd 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) (ED 50 ≈ 70 pmol/kg) was the same as that of oxyntomodulin (ED 50 ≈ 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 pcptidcs. its maximal inhibition (at 15 nmol/kg) was the same as thit of oxyntomodulin-(19–37). Thus, oxyntomodlin-(30–37) was as efficient as the longer molecules but as ≈150-fold less potent than oxyntomodulin. The MCR for oxyntomodulin-(30–37) was ≈ 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. Neither oxyntomodulin-(30–37), oxyntomodulin nor oxyntomodulin-(19–37) had any effect on basal acid secretion.