前列腺素E受体4拮抗剂与透明质酸钠在间质性膀胱炎/膀胱疼痛综合征大鼠模型中的作用比较

Prostaglandin E2 receptor 4 receptor antagonist vs.sodium hyaluronate for hyaluronidase-induced interstitial cystitis in rats

目的 比较前列腺素E受体4（EP4）拮抗剂与透明质酸钠对透明质酸酶诱导的大鼠间质性膀胱炎（IC）的作用.方法 将50只成年雌性Sprague-Dawley（SD）大鼠（200 ～ 250 g）,分为对照组15只（膀胱灌注生理盐水）,模型组15只（膀胱灌注透明质酸酶）,拮抗组10只（AH23848）,黏膜保护组10只（透明质酸钠）.采用长期（1个月）间歇灌注透明质酸酶（4 g/L）构建大鼠IC/膀胱疼痛综合征（BPS）模型,尿流动力学检测膀胱功能,离体膀胱检测膀胱张力,实时定量聚合酶链反应检测炎性因子信使核糖核酸（mRNA）表达,免疫组织化学检测膀胱EP4和P物质蛋白表达.结果 与对照组比较,模型组大鼠两次排尿间隔缩短[（145.62 ±44.96）s],膀胱容量降低[（0.40±0.07） ml],炎性因子白细胞介素（IL）-6、IL-1β mRNA表达升高,膀胱中EP4受体和P物质表达升高（P＜0.05）.AH23848和透明质酸钠处理模型大鼠后,两次排尿间隔均延长,膀胱容量均提高,IL-6、IL-1β的mRNA表达均降低（P＜0.05）.但与透明质酸钠比较,AH23848能更好的延长两次排尿间隔[（427.52 ±54.24）s],增加膀胱容量[（1.19±0.09）ml].同时AH23848能明显降低膀胱P物质的表达（P＜0.05）,而透明质酸钠不能.另外模型组离体膀胱加入AH23848后,出现明显舒张[抑制率为（19.75±3.59）％,P＜0.05].结论 与透明质酸钠比较,EP4受体拮抗剂AH23848能直接舒张膀胱肌,改善透明质酸酶诱导的大鼠尿频症状,同时缓解膀胱疼痛.

Objective To compare the effects of prostaglandin E2 receptor 4 （EP4） receptor antagonist vs.sodium hyaluronate on the hyaluronidase-induced interstitial cystitis in rats.Methods Fifty Sprague-Dawley rats were randomly divided into control group （15 rats,intravesical normal saline）,model group （15 rats,intravesical hyaluronidase）,antagonist group （10 rats,intraperitoneal AH23848）,and mucosa protection group （10 rats,intraperitoneal hyaluronic acid）.The rat interstitial cystitis models were created by long-term （1 month） intermittent intravesical hyaluronidase （4 g/L）.Voiding patterns were investigated by cystometry.Rat bladder strips were used to examine bladder tension in vitro.The mRNA levels of interleukin-6 and interleukin-1 beta were analyzed by real-time reverse transcription polymerase chain reaction.The protein levels of EP4 and substance P in the bladder were determined by immunohistochemistry.Results As compared with control group,the intercontraction intervals [（145.62 ± 44.96） s] and bladder capacity [（0.40 ±0.07） ml] were significantly decreased,and the mRNA levels of interleukin （IL）-6 and IL-1 β,the protein levels of EP4 receptor and substance P were significantly increased in model group （all P ＜ 0.05）.After administration of EP4 antagonist AH23848 and sodium hyaluronate,the intercontraction intervals and bladder capacity were significantly increased,and the mRNA levels of IL-6 as well as IL-1 β were significantly decreased （all P ＜ 0.05）.AH23848 showed a better effect on increasing the intercontraction intervals [（427.52 ± 54.24） s] and bladder capacity [（1.19 ± 0.09） ml] than sodium hyaluronate.AH23848 could also significantly decrease the expression of substance P in the bladder,while sodium hyaluronate had no such effect.Furthermore,AH23848 could relax the KCl-induced contraction of bladder strips from rats induced by hyaluronidase [inhibition with （19.75 ± 3.59） ％,P ＜ 0.05].Conclusion As compared with sodium hyaluronate,EP4 receptor antagonist AH23848 could relax KCl-induced contraction of bladder strips,improve the frequent micturition of hyaluronidase-induced rats,and ameliorate the bladder pain.Consequently,its antagonist may act as a new therapeutic target for interstitial cystitis/bladder pain syndrome （IC/BPS）.