CHOLECYSTOKININ TYPE-A RECEPTORS MEDIATE INTESTINAL FAT-INDUCED INHIBITION OF ACID-SECRETION THROUGH SOMATOSTATIN-14 IN DOGS

This study was designed to examine whether one or both principle molec ular forms of somatostatin (SLI), somatostatin-28 (S-28) and somatosta tin-14 (S-14), mediate inhibition of stimulated gastric acid by intest inal fat and to determine whether the mode of action includes activati on of type A cholecystokinin (CCK receptors in conscious dogs. SLI mol ecular forms were separated by gel filtration chromatography after ext raction of acidified plasma on octadecyl silyl cartridges and quantifi ed by RIA. Basal plasma levels of S-28 and S-14 were 4.1+/-0.6 and 3.6 +/-0.3 fmol/ml, respectively. Intraduodenal perfusion with a 10% fat e mulsion increased plasma S-28 by 6.3+/-1.2 fmol/ml (P < 0.01) and S-14 by 17.8+/-2.6 fmol/ml (P < 0.001), and suppressed by 76+/-3% (P < 0.0 01) gastrin (150 pmol/kg.h)-stimulated gastric acid. Blockade of type A CCK receptors with MK-329 (75 mu g/kg, iv) abolished S-28 and S-14 r esponses (both P < 0.001) and completely reversed the inhibitory effec t of gastric acid produced by intraduodenal fat, Intravenous infusions of S-14 dose-dependently inhibited gastrin-stimulated secretion with an estimated 50% inhibitory dose of 125 pmol/kg.h that achieved an inc remental plasma S-14 rise of 40+/-2 fmol/ml; infusions of S-28 at 30 p mol/kg.h increased plasma S-28 by 47+/-3 fmol/ml without altering acid output. The SLI antagonist cyclo-[7-aminoheptanoly-Phe-D-Trp-Lys-Thr( BZL)] (CyCam) reversed by 89+/-4% (P < 0.001) exogenous S-14-induced i nhibition of gastrin-stimulated acid secretion, but did not influence gastric acid output after the infusion of S-28. CyCam also reversed by 139+/-9% (P < 0.001) the early phase of fat-induced acid inhibition; in the late phase, CyCam treatment was associated with a further 2-fol d elevation of plasma peptide-YY (PYY) to 102+/-6 fmol/ml (P < 0.001) and a 75+/-5% suppression of gastric acid. Simulation of this plasma P YY increment with infusions of PYY at 50 pmol/kg.h inhibited by 44+/-5 % gastrin-stimulated acid secretion. These results indicate that in co nscious dogs, endogenous CCK mediation of intraintestinal fat-induced inhibition of stimulated acid secretion occurs in part through CCK typ e A receptor activation of S-14 secretion, Modulation of gastric acid by S-14 includes both inhibition and attenuation of further suppressio n via counterregulation of PYY secretion.