Interaction among Secretagogues on Pepsinogen Secretion from Rat Gastric Chief Cells

Abstract

We examined the interaction among secretagogues that stimulate pepsinogen secretion through different pathways in vivo and in vitro. In in vitro study, a combined administration of secretin and carbachol or cholecystokinin octapeptide (CCK-8) to the culture medium of chief cells potentiated pepsinogen secretion. Moreover, the response induced by carbachol or CCK-8 with forskolin was greater than that with secretin. We examined the interaction among receptor-related second mediators, and found that carbachol-or CCK-8-induced intracellular Ca²⁺ concentration ([Ca²⁺]i) increase was not affected by secretin or forskolin. Both these substances, however, significantly reduced secretin-induced cAMP production. On the contrary, CCK-8 significantly increased forskolin-induced cAMP production, while carbachol increased it slightly. Calcium ionophore, A23187, or protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), did not alter secretin-or forskolin-induced cellular cAMP production ; and the reductive effect of carbachol or CCK-8 on secretin-induced cAMP production was restored by their competitive antagonists, atropine or lorglumide. EC₅₀ of those antagonists was almost the same value as IC₅₀ on pepsinogen secretion and [Ca²⁺] i increase. These results indicate that secretin-induced cAMP production is interfered with by receptor related agonists like CCK-8 and carbachol. It may be suggested that there is a kind of "cross-talk, " between the adenylate cyclase system, that is, the secretin receptor, and carbachol or CCK-8 receptor. The interactions between secretin and other secretagogues (carbachol, CCK-8, tetragastrin and histamine) were examined using the perfused rat stomach. The infusion of CCK-8 induced high pepsin secretion initially, which gradually decreased ; with a simultaneous injection of secretin, however, high pepsin secretion was maintained. High pepsin secretion induced by an infusion of carbachol was obtained when secretin was injected simultaneously. Although tetragastrin or histamine did not stimulate significant pepsin secretion, pepsinogen secretion was stimulated if secretin injected simultaneously. These results suggest that pepsinogen secretion in the rat is not controlled only by pepsinogen secretagogues but by its combination with acid secretagogues.