Takeuchi K, Aihara E, Sasaki Y, Nomura Y, Ise F
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan.
J Physiol Pharmacol. 2006 Dec;57(4):661-76.
We investigated the cyclooxygenase (COX) isoforms as well as prostaglandin E receptor EP subtypes responsible for acid-induced gastric HCO(3)(-) secretion in rats and EP receptor-knockout (-/-) mice. Under urethane anesthesia, a chambered stomach (in the presence of omeprazole) was perfused with saline, and HCO(3)(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. Mucosal acidification was achieved by exposing the stomach for 10 min to 50 or 100 mM HCl. Acidification of the mucosa increased the secretion of HCO(3)(-) in the stomach of both rats and WT mice, in an indomethacin-inhibitable manner. The acid-induced gastric HCO(3)(-) secretion was inhibited by prior administration of indomethacin and SC-560 but not rofecoxib in rats and mice. Acidification increased the PGE(2) content of the rat stomach, and this response was significantly attenuated by indomethacin and SC-560 but not rofecoxib. This response was also attenuated by ONO-8711 (EP1 antagonist) but not AE3-208 (EP4 antagonist) in rats and disappeared in EP1 (-/-) but not EP3 (-/-) mice. PGE(2) increased gastric HCO(3)(-) secretion in both rats and WT mice, and this action was inhibited by ONO-8711 and disappeared in EP1 (-/-) but not EP3 (-/-) mice. These results support a mediator role for endogenous PGs in the gastric response induced by mucosal acidification and clearly indicate that the enzyme responsible for production of PGs in this process is COX-1. They further show that the presence of EP1 receptors is essential for the increase in the secretion of HCO(3)(-) in response to mucosal acidification in the stomach.
我们研究了环氧化酶（COX）同工型以及负责大鼠和EP受体基因敲除（-/-）小鼠中酸诱导胃HCO₃⁻分泌的前列腺素E受体EP亚型。在氨基甲酸乙酯麻醉下，用含奥美拉唑的生理盐水灌注有腔胃，并使用pH计法并添加2 mM盐酸在pH 7.0时测量HCO₃⁻分泌。通过将胃暴露于50或100 mM盐酸中10分钟来实现粘膜酸化。粘膜酸化以消炎痛可抑制的方式增加了大鼠和野生型小鼠胃中HCO₃⁻的分泌。在大鼠和小鼠中，预先给予消炎痛和SC-560可抑制酸诱导的胃HCO₃⁻分泌，但罗非昔布则无此作用。酸化增加了大鼠胃中PGE₂的含量，消炎痛和SC-560可显著减弱这种反应，但罗非昔布则无此作用。在大鼠中，ONO-8711（EP1拮抗剂）也可减弱这种反应，但AE3-208（EP4拮抗剂）则无此作用，并且在EP1（-/-）小鼠中这种反应消失，但在EP3（-/-）小鼠中未消失。PGE₂增加了大鼠和野生型小鼠胃中HCO₃⁻的分泌，ONO-8711可抑制这种作用，并且在EP1（-/-）小鼠中消失，但在EP3（-/-）小鼠中未消失。这些结果支持内源性前列腺素在粘膜酸化诱导的胃反应中起介质作用，并清楚地表明在此过程中负责前列腺素产生的酶是COX-1。它们进一步表明，EP1受体的存在对于胃中粘膜酸化引起的HCO₃⁻分泌增加至关重要。
