Impaired duodenal bicarbonate secretion and mucosal integrity in mice lacking prostaglandin E-receptor subtype EP3

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Abstract

Background and Aims: To examine the involvement of EP3 receptors in physiological regulation of duodenal HCO3- secretion, we disrupted the gene encoding EP receptors in mice by homologous recombination and evaluated acid- induced HCO3- secretion, which is physiologically important in the mucosal defense against acid injury, using EP1- and EP3-receptor knockout mice. Methods: The experiments were performed in the following 3 groups of mice after 18 hours of fasting: wild-type [WT (+/+)] mice, EP1-receptor knockout [EP1 (-/-)] mice, and EP3-receptor knockout [EP3 (-/-)] mice. Under urethane anesthesia, the proximal duodenal loop was perfused with saline that was gassed with 100% O2, heated at 37°C, and kept in a reservoir, and HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 5 mmol/L HCI. Results: The duodenum of WT (+/+) mice increased HCO3- secretion in response to luminal perfusion of prostaglandin E2 and forskolin as well as mucosal acidification. The latter effect was significantly inhibited by prior administration of indomethacin. HCO3- response to acid was observed in EP1 (-/-) mice but disappeared totally in EP3 (-/-) animals, although the acidification increased mucosal PGE2 generation by similar degrees in all groups. The HCO3- stimulatory action of PGE2 was also absent in EP3 (-/-) but not EP1 (-/-) mice, but forskolin effect was observed in both groups of animals, similar to WT (+/+) mice. Perfusion of the duodenum with 20 mmol/L HCI for 4 hours caused severe damage in EP3 (-/- ) mice and WT (+/+) animals pretreated with indomethacin, but not in EP1 (- /-) mice. Conclusions: The presence of EP3-receptors is essential for maintaining duodenal HCO3-secretion and mucosal integrity against luminal acid.

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Takeuchi, K., Ukawa, H., Kato, S., Furukawa, O., Araki, H., Sugimoto, Y., … Narumiya, S. (1999). Impaired duodenal bicarbonate secretion and mucosal integrity in mice lacking prostaglandin E-receptor subtype EP3. Gastroenterology, 117(5), 1128–1135. https://doi.org/10.1016/S0016-5085(99)70398-7

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