title: Gastric cytoprotection by prostaglandin E₂ and prostacyclin: relationship to EP1 and IP receptors.
abstract: Endogenous prostaglandins (PGs) play a role in modulating mucosal integrity and have various functions in the stomach, with E type PGs being the most effective. PGE₂ provides gastric cytoprotection against damage induced in rats by HCl/ethanol, indomethacin, or acid back-diffusion after barrier disruption. These effects were mimicked by EP1 agonists and/or attenuated by an EP1 antagonist, and disappeared in EP1 (-/-) mice. Furthermore, the adaptive cytoprotection induced by a mild irritant was attenuated by the EP1 antagonist and indomethacin. Capsaicin also provides gastric protection against HCl/ethanol, and its action was mitigated by indomethacin and sensory deafferentation, but not by the EP1 antagonist. Similar results were obtained using mice lacking various EP receptor subtypes; i.e., PGE₂ failed to provide both direct and adaptive cytoprotection in EP1 (-/-) mice, while capsaicin-induced protection was observed in EP1 (-/-) mice, but disappeared in IP (-/-) mice. The effects of PGE₂ on various gastric functions are mediated by different EP receptor subtypes; inhibition of acid secretion (EP3) and motility (EP1), stimulation of mucus secretion (EP4) and HCO₃⁻ secretion (EP1), and an increase in mucosal blood flow (EP2/EP4). In conclusion, the presence of EP1 receptors is essential to the protective action of PGE₂, either generated endogenously or administered exogenously, against HCl/ ethanol or indomethacin, and this action is functionally associated with the inhibition of gastric motility. Endogenous PGs also contribute to maintaining mucosal integrity after barrier disruption through an increase in mucosal blood flow, which occurs via sensory neurons influenced by activation of the EP1 receptor.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp.
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D019610:Cytoprotection / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011982:Receptors, Prostaglandin / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011982:Receptors, Prostaglandin; D000431:Ethanol; D011464:Epoprostenol; D015232:Dinoprostone