Role of Prostaglandin E Receptor Subtypes in Gastroduodenal HCO3 - Secretion

Abstract

Gastroduodenal HCO3- secretion is a key process that aids in preventing acid-peptic injury. Endogenous prostaglandins (PGs) play a particularly important role in the local control of this secretion. The secretion of HCO3- in both the stomach and duodenum was increased in response to PGE2 as well as mucosal acidification, the latter occurring with concomitant enhancement of mucosal PG generation. These HCO3- responses in the duodenum were markedly reduced by prior administration of the EP4 antagonist in rats, and profoundly decreased in the animals lacking EP3 receptors but not EP1 receptors. In contrast, gastric HCO3- responses induced by PGE2 and mucosal acidification were prevented by the EP1 antagonist and disappeared in EP1, but not EP3-knockout mice. Consistent with these findings, duodenal HCO3- secretion was stimulated by both EP3 and EP4 agonists but not EP1 or EP2 agonists, while gastric HCO3- secretion was increased by the EP1 agonist but not EP2, EP3 or EP4 agonists. In addition, the HCO3- stimulatory action of sulprostone (EP1/EP3 agonist) in the stomach was inhibited by the Ca2+ antagonist verapamil but not affected by IBMX, the inhibitor of phosphodiesterase, while that in the duodenum was inhibited by verapamil and enhanced by IBMX. Forskolin, the stimulator of adenylate cyclase, increased HCO3- secretion in the duodenum but not the stomach. Thus, the HCO3- stimulatory action of PGE2 in the duodenum is mediated by both EP3 and EP4 receptors being coupled intracellularly with both Ca2+ and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca2+.

Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion

“…Both agonists are endogenous to the intestine and known to be involved in both physiological functions and pathological conditions in the gut. PGE 2 may act more potently among the secretagogues we tested because it may stimulate both cAMP-mediated (EP4 receptor) and Ca 2+ -mediated (EP3 receptor) pathways as reported for duodenal secretion (38), as well as effectively stimulating intestinal HCO 3 -secretion (36). Moreover, since mucus in the small intestine derives from different cells (crypts and villi), PGE 2 may activate multiple cell types and/or multiple pathways in the same cell.…”

“…Indeed, HCO 3 --free fluid secreted from the crypts would likely prevent HCO 3 --containing luminal perfusate from entering these structures during stimulation. We do not know the source of secreted HCO 3 -, but it seems likely that it originates from either the base of the villi and/or the crypts (45), possibly via independent mechanisms (36,38). Although there are reports that CFTR expression is present in intestinal goblet cells (46, 47), we would not expect these cells to be the main source of secreted HCO 3 -, since they do not exhibit hallmark features of electrolyte-transporting cells.…”

Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease

“…Prostaglandin E2 (PGE2) induces protection by stimulating release of bicarbonate and mucus. The bicarbonate stimulatory effect of PGE2 is mediated by endogenous prostaglandin (EP)-1 receptors coupled with Ca 2+ along the gastric mucosa, and EP-3 and EP-4 coupled intracellularly with Ca 2+ and cyclic AMP in the duodenal mucosa 1,2. As such, prostaglandin analogs, misoprostol, H2-receptor antagonists (H2RA), and proton pump inhibitors have been evaluated in randomized controlled trials for the prevention of chronic NSAID-induced upper gastrointestinal toxicity.…”

Antiulcer Potential of a Standardized Extract of Red Orange Juice in the Rat

“…In addition, prostaglandins enhance mucosal blood flow and stimulate secretion of mucus and bicarbonate. [1,2,3] It is generally accepted that gastric ulcer is due to an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandins, nitric oxide, other peptides, and growth factors) and aggressive factors (acid and pepsin). Although patients with gastric ulcers have normal or even lower acid production than control subjects, ulcer rarely, if ever, occurs in the complete absence of acid.…”