Prostaglandin EP receptor subtypes involved in regulating HCO(3)(-) secretion from gastroduodenal mucosa.
Gastroduodenal HCO(3)(-) secretion is a key process that aids in preventing acid-peptic injury. The HCO(3)(-) secretion in rats and mice was increased in response to PGE(2) as well as mucosal acidification, the latter response occurring with a concomitant enhancement of mucosal PG production. The duodenal responses to PGE(2) and acid were decreased in mice lacking EP3 receptors and reduced by coadministration of an EP3 or EP4 antagonist in rats, complete inhibition being observed when the EP3 and EP4 antagonists were given together. By contrast, the gastric responses disappeared in EP1-knockout mice and were prevented by an EP1 antagonist but not other EP antagonists. Furthermore, duodenal HCO(3)(-) secretion was stimulated by the EP3 and EP4 agonists, whereas gastric HCO(3)(-) secretion was increased only by the EP1 agonist. In addition, the HCO(3)(-) stimulatory effect of sulprostone (an EP1/EP3 agonist) in the duodenum was inhibited by verapamil, a Ca(2+) antagonist, and enhanced by isobutyl- methylxanthine, a phosphodiesterase (PDE) inhibitor, but the response in the stomach was inhibited by verapamil and not affected by isobutylmethylxanthine. In the mouse duodenum but not stomach, the response to PGE(2) was potentiated by both vinpocetine (a PDE1 inhibitor) and cilostamide (a PDE3 inhibitor). These results suggest that the HCO(3)(-) stimulatory effect of PGE(2) in the duodenum is mediated by both EP3 and EP4 receptors, being coupled intracellularly with Ca(2+) and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca(2+). In addition, both PDE1 and PDE3 are involved in the regulation of duodenal HCO(3)(-) secretion.
Takeuchi
Koji
K
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607, Japan. takeuchi@mb.kyoto-phu.ac.jp
Koyama
Masafumi
M
Hayashi
Shusaku
S
Aihara
Eitaro
E
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism* / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D011459:Prostaglandins E, Synthetic / Q000819:agonists / Q000037:antagonists & inhibitors; D020011:Protective Agents / Q000737:chemistry; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013270:Stomach / Q000187:drug effects
D001639:Bicarbonates; D011459:Prostaglandins E, Synthetic; D020011:Protective Agents; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype