Adaptive gastric cytoprotection is mediated by prostaglandin EP1 receptors: A study using rats and knockout mice

Endogenous prostaglandins (PGs) play a central role in adaptive cytoprotect ion induced in the stomach by mild irritants. In the present study, we used taurocholate (TC) as a mild irritant in both rats acid EP-receptor knockou t mice, and examined which EP receptor is responsible for the adaptive gast ric cytoprotection. Gastric lesions were induced by p.o. administration of HCl/ethanol (60% ethanol in 150 mM HCl). TC (5-20 mM) or PGE2 was administe red p.o. 30 min before HCl/ethanol. HCl/ethanol-induced gastric lesions wer e dose dependently prevented by TC, and the effect at 20 mM was equivalent to that induced by PGE2 at 0.3 mg/kg. The protective effect of TC was signi ficantly attenuated by indomethacin as well as ONO-AE-829, the EPI antagoni st, but not by either NS-398, the selective cyclooxygenase (COX)-2 inhibito r, or chemical ablation of capsaicin-sensitive sensory neurons. Likewise, t he protective action of PGE2 was also antagonized by ONO-AE-829 but not che mical deafferentation. TC significantly increased PGE2 contents in the stom ach, with or without chemical deafferentation, and this effect was blocked in the presence of indomethacin but not NS-398 or ONO-AE-829. TC increased the mucosal PGE2 contents similarly in both wild-type and knockout mice lac king EP1 or EP3 receptors, yet the protective action of TC against HCl/etha nol was observed in both wild-type and EP3 receptor knockout mice, but not in mice lacking EP1 receptors. The present findings confirmed a role for en dogenous PGE2 produced by COX-1 in adaptive gastric cytoprotection and sugg ested that this action is mediated by activation of EP1-receptors but not a ssociated with capsaicin-sensitive afferent neurons.