Characterization of CCKA receptor mediated pepsinogen secretion in porcine chief cells

Cholecystokinin octapeptide (CCK-8s) is an endogenous stimulus of gastric pepsinogen secretion. Previous studies with isolated guinea pig chief cells indicated that this process is mediated through the CCKA receptor subtype, with an additional contribution from CCKB receptors. For comparison, we examined the mechanism of CCK-8s stimulated pepsinogen secretion in a larger nonrodent species, using highly enriched porcine chief cells as a functional in vitro model. Porcine chief cells responded weakly to stimulation by CCK-8s alone, but the efficacy was markedly enhanced in the presence of 10 mumol l-1 forskolin. Under these conditions, pepsinogen secretion was potently stimulated by CCK-8s and the CCKA receptor selective heptapeptide, A-71,378 (EC50 = 4.7 and 33 nmol l-1), but not by CCKB receptor selective agonists. The prototype CCKA receptor selective antagonist L-364,718 blocked pepsinogen secretion with approximately 2,000-fold higher affinity than the CCKB receptor selective analogue, L-365,260. This functional profile was consistent with the affinity rank order of all tested compounds at CCKA-receptor-like [125I]-BH-CCK-8s binding sites in the porcine gastric mucosa. Comparison with cloned CCKA receptors from other species revealed that the receptors mediating pepsinogen secretion in the pig have similar pharmacology, possibly with slight differences in agonist potencies. In contrast to the guinea pig, porcine CCKB receptors appear to have no direct role in pepsinogen secretion.