Regulation by Vasoactive Intestinal Peptide, Histamine, Somatostatin-14 and -28 of Cyclic Adenosine Monophosphate Levels in Gastric Glands Isolated from the Guinea Pig Fundus or Antrum*

Abstract

Studies were conducted to explore the effects of vasoactive intestinal peptide (VIP), histamine, somatostatin-14 and -28 (S-14 and S-28), and prostaglandin E₂ (PGE₂) on cAMP production in gastric glands isolated from the guinea pig. VIP (EC₅₀ = 5 × 1O^-10 M) and PGE₂ (EC₅₀ = 10^-8 M) induced cAMP accumulation in glands isolated by means of EDTA from the fundus or antrum. The structurally related peptides PHI (peptide with N-terminal histidine and C-terminal isoleucine amide) and secretin also increased cAMP production in the system, but with 200 to 2000 times lower potencies than VIP. Combinations of VIP with PHI or secretin do not produce additive stimulation, indicating that PHI or secretin interact with the receptor-cAMP system highly sensitive to VIP. Histamine was about 10 times more potent in fundus (EC₅₀ = 10^-5 M) than in antrum (EC₅₀ = 9 × 10^-6 M) and did not produce any stimulation in enterocytes isolated from the upper part of the duodenum. Complete inhibitions caused by the H₂ receptor antagonist cimetidine (K_i = 0.15–0.16 × 10^-6 M) (K_i is the inhibition constant) or by the Hi receptor antagonist diphenhydramine (DPH) (K_i = 13–17 × 10^-6 M) indicate that H interacts with typical H₂ receptors mediating adenylate cyclase activation in fundic (K_a = 10^-5 M) (K_a is the association constant) or antral membranes (K_a = 3 × 10^-5 M). In fundus, S-14 inhibited partially (about 60%) cAMP production evoked by H or by its Hi or H₂ agonists. The kinetics and the inhibitory potencies (2 × 10^-8 M) or efficacies of S-14 and - 28 were identical. No effect of S-14 was found on basal or on cAMP production induced by VIP or PGE₂ in either fundic or antral glands or by H in antral glands. The results support the hypothesis of a regulatory role for VIP and/or secretin in mucous and/or peptic secretions via a cAMP-dependent mechanism in gastric mucosa in mammals. Second, we propose that S-14 as well as S-28 may inhibit gastric acid secretion by a direct and selective control of H-induced cAMP production in parietal cells, through a common recognition site (receptor?) distinct from the H ₂receptor. Third, not only parietal cells, but also nonparietal cells of the antrum possess an H₂ receptor-cAMP system. This finding could be related to the in vivo regulation by cimetidine of endocrine (somatostatin) and exocrine (pepsin) secretions by the stomach.