Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
J Physiol Pharmacol. 2013 Aug;64(4):453-63.
The extracellular calcium-sensing receptor (CaSR), a G protein-coupled cell receptor cloned from bovine parathyroid, has been demonstrated to play a regulatory role in various functions of the gastrointestinal tract. In the present study, we examined the effect of cinacalcet, a drug that acts as a calcimimetic through the allosteric activation of CaSR, on the loxoprofen-induced small intestinal lesions and investigated the mechanisms involved in the protective action. Male Sprague-Dawley rats were used without fasting. The animals were administered loxoprofen p.o. and euthanized 24 hours later and the intestinal mucosa was examined for lesions. Cinacalcet was given p.o. twice, 30 min before and 6 h after loxoprofen. Loxoprofen caused hemorrhagic lesions in the small intestine, accompanied by the upregulation of enterobacterial invasion, myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS)/tumor necrosis factor α (TNF-α) expression as well as the downregulation of Muc2 expression. Prior administration of cinacalcet dose-dependently and significantly reduced the severity of these lesions in response to loxoprofen, with concomitant suppression of the changes in bacterial invasion, iNOS/TNF-α as well as Muc2 expression, and myeloperoxidase activity. Cinacalcet also significantly reversed a decrease in mucus secretion and fluid secretion in the small intestine caused by loxoprofen, but had no effect on the intestinal hypermotility or prostaglandin E₂ deficiency caused by loxoprofen. These results suggest that cinacalcet protects the small intestine against loxoprofen-induced damage, and this effect may be functionally associated with an increase in fluid secretion and a reversal of downregulation of Muc2 expression caused by loxoprofen, resulting in suppression of bacterial invasion and iNOS/TNF-α expression, the major pathogenic events in nonsteroidal antiinflammatory drugs-induced small intestinal ulceration.
细胞外钙敏感受体（CaSR）是从牛甲状旁腺克隆的 G 蛋白偶联细胞受体，已被证明在胃肠道的各种功能中发挥调节作用。在本研究中，我们研究了西那卡塞（一种通过变构激活 CaSR 发挥钙敏感受作用的药物）对洛索洛芬引起的小肠损伤的作用，并探讨了其保护作用的机制。雄性 Sprague-Dawley 大鼠无需禁食。动物给予洛索洛芬灌胃，24 小时后处死，检查肠黏膜损伤。西那卡塞两次给予灌胃，洛索洛芬前 30 分钟和 6 小时后给予。洛索洛芬引起小肠出血性损伤，伴有肠杆菌侵袭、髓过氧化物酶（MPO）活性和诱导型一氧化氮合酶（iNOS）/肿瘤坏死因子-α（TNF-α）表达上调，以及 Muc2 表达下调。西那卡塞预先给药可剂量依赖性地显著减轻洛索洛芬引起的这些损伤的严重程度，同时抑制细菌侵袭、iNOS/TNF-α 以及 Muc2 表达和 MPO 活性的变化。西那卡塞还显著逆转了洛索洛芬引起的小肠黏液分泌和液体分泌减少，但对洛索洛芬引起的肠道蠕动过度或前列腺素 E₂ 缺乏无影响。这些结果表明，西那卡塞可保护小肠免受洛索洛芬引起的损伤，其作用可能与增加液体分泌和逆转洛索洛芬引起的 Muc2 表达下调有关，从而抑制细菌侵袭和 iNOS/TNF-α 表达，这是非甾体抗炎药引起的小肠溃疡的主要发病事件。
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