BOTH CCK-A AND CCK-B/GASTRIN RECEPTORS MEDIATE PEPSINOGEN RELEASE IN GUINEA-PIG GASTRIC GLANDS

We evaluated the affinity of cholecystokinin octapeptide (CCK-8), gastrin, and subtype-selective CCK agonists for CCK/gastrin receptors and compared it with the ability of these peptides to stimulate phosphoinositide (PI) hydrolysis and pepsinogen release in guinea pig gastric glands. Competitive binding studies using I-125-labeled Bolton-Hunter-CCK-8 and I-125-gastrin showed the presence of CCK-B/gastrin receptors in gastric glands and dispersed chief cells. In contrast, the potency of peptides in stimulating PI hydrolysis in both gastric glands and dispersed chief cells displayed a profile similar to CCK-A receptors found in pancreatic acini, i.e., CCK-8 = A 71378 > A 71623 > A 70874 >> A 72962 = CCK-8 (desulfated) > gastrin II > gastrin I. In general, the rank order of potency of peptides for stimulation of PI hydrolysis correlated well with their ability to stimulate pepsinogen release. At concentrations >10-mu-M, efficacies of gastrin I and II in stimulating pepsinogen release from gastric glands were near 90% of the maximal activity of CCK-8. The inhibitory potency of MK-329, a selective CCK-A receptor antagonist, was similar against either CCK-8 (10 nM) or gastrin I (10-mu-M), except that a minor portion (approximately 30-40%) of gastrin I-induced pepsinogen release was insensitive to MK-329. The MK-329-insensitive component was inhibited by CI-988, a potent and selective CCK-B/gastrin receptor antagonist. Our results suggest, in contrast to a previous study [Cherner et al. Am. J. Physiol. 254 (Gastrointest. Liver Physiol. 17): G151-G155, 1988] that a CCK-A-like receptor on gastric chief cells is responsible for mediating most of the PI-hydrolyzing and pepsinogen-releasing properties of CCK- and gastrin-related peptides. In addition, a small portion (30-40%) of the gastrin-induced pepsinogen secretion appears to involve the CCK-B/gastrin receptor.