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.

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 HCl.

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 HCl for 4 hours caused severe damage in EP₃ (−/−) mice and WT (+/+) animals pretreated with indomethacin, but not in EP₁ (−/−) mice.

The presence of EP₃-receptors is essential for maintaining duodenal HCO₃⁻ secretion and mucosal integrity against luminal acid. GASTROENTEROLOGY 1999;117:1128-1135