PDE inhibitors on acid secretion and histamine release induced by pituitary adenylate cyclase activating polypeptide (PACAP), a biologically active neuropeptide with a potent stimulatory effect on histamine release from ECL cells (15-18). MATERIALS AND METHODS Animals

The central role of histamine in gastric acid secretion has been studied extensively (1-6). Gastric histamine is released from enterochromaffin-like (ECL) cells in rats and subsequently stimulates acid secretion via the activation of histamine H2 receptors on parietal cells (7, 8). Histamine also stimulates the secretion of acid in the stomach via the activation of adenylate cyclase and an increase in the intracellular level of 3’, 5’-cyclic adenosine monophosphate (cAMP) (1, 2, 4). Because cAMP is degraded into inactive metabolites via hydrolysis by phosphodiesterase (PDE), it is possible that PDE affects the response to histamine by altering the levels of this nucleotide. Indeed, the acid response to histamine was reportedly potentiated by theophilline (4). At present, the PDE in mammalian tissues has been subdivided into 11 isozymes, each derived from separate gene families and having pharmacologically distinct roles (9). PDE1 to PDE5 have been well characterized, and selective inhibitors of these isozymes are used for the treatment of heart disease, depression, asthma, inflammatory disease, and erectile dysfunction (10-12). To disclose the profiles of the subtypeselective PDE inhibitors would be helpful for eliminating the adverse influences of these agents in the body, including the gastrointestinal tract. We recently found using isolated mouse stomachs that the response of HCO3to nitric oxide (NO) was regulated by both PDE1 and PDE5, while other subtypes of PDE had no effect (13). However, it remains unexplored which PDE isozyme(s) is involved in the regulation of gastric acid secretion. In the present study, we examined the effects of subtypeselective inhibitors of PDE1 to PDE5 on the secretion of acid in response to histamine in the isolated mouse stomach and investigated which isozymes of PDE are involved in the local regulation of gastric acid secretion. Since the release of histamine from ECL cells is known to be regulated by cAMP, in addition to Ca2+ (4, 14), we also examined the influences of these PDE inhibitors on acid secretion and histamine release induced by pituitary adenylate cyclase activating polypeptide (PACAP), a biologically active neuropeptide with a potent stimulatory effect on histamine release from ECL cells (15-18).