Angelico Patrizia, Guarneri Luciano, Velasco Cristina, Cova Rita, Leonardi Amedeo, Clarke David E, Testa Rodolfo
Pharmaceutical R & D Division, Recordati SpA, Via M. Civitali 1, 20148 Milan, Italy.
BJU Int. 2006 Apr;97(4):837-46. doi: 10.1111/j.1464-410X.2006.06003.x.
To investigate the role of cyclooxygenase (COX) isozymes (COX-1 and -2) in the regulation of bladder volume capacity (BVC) in several rat urodynamic models, using a selection of nonsteroidal anti-inflammatory drugs (NSAIDs), some selective for COX-2, correlating the potency of the tested compounds in the urodynamic models and their in vitro potency as inhibitors of COX isozymes, to verify the relative importance of the different isozymes.
The effects of an i.v. administration of several nonselective and selective COX-2 inhibitors (indomethacin, meloxicam, naproxen, aspirin, paracetamol, flurbiprofen, nimesulide, NS-398, celecoxib, rofecoxib and L 745337) on bladder filling and voiding were evaluated in conscious and anaesthetized rats by cystometry. The cystometry was done in conscious rats 1 day after catheter implantation, by filling the bladder with dilute acetic acid (0.2%) or saline, and again with saline 5 days after catheterization. Effects on isovolumic bladder contractions in anaesthetized rats were also evaluated.
All the NSAIDs tested dose-dependently increased BVC; their potency at increasing BVC during infusion of the bladder with acetic acid was similar to that evaluated with saline on cystometry 1 day after catheterization. When a nonselective (naproxen) and a selective (nimesulide) COX-2 inhibitor were tested in rats with bladders infused with saline 5 days after catheterization, their effects on BVC were significantly lower than those evaluated at 1 day. All tested compounds dose-dependently inhibited isovolumic bladder contractions in anaesthetized rats. There was a good correlation between the potency in inhibiting the isovolumic bladder contractions in anaesthetized rats and in increasing BVC during cystometry in conscious rats with the bladder infused with acetic acid. The potency of the compounds in the cystometry model with bladders infused with acetic and in the isovolumic bladder voiding contractions correlated well with COX-2 inhibition, but not COX-1.
Both nonselective and COX-2 selective inhibitors are more active in inhibiting the micturition reflex in rats with bladder overactivity caused by bladder irritation than in normal rats. The potency of the anti-inflammatory compounds in inhibiting bladder overactivity induced by chemical or surgical irritation, and their activity in a cystometrographic model practically independent of bladder irritation (isovolumic bladder contractions in anaesthetized rats), was related to the potency as inhibitors of COX-2 isozyme. This suggests that the involvement of prostaglandins in the micturition reflex in rats is mainly mediated by this isozyme.
在几种大鼠尿动力学模型中，使用多种非甾体抗炎药（NSAIDs），其中一些对COX - 2具有选择性，研究环氧化酶（COX）同工酶（COX - 1和 - 2）在调节膀胱容量（BVC）中的作用，将受试化合物在尿动力学模型中的效力与其作为COX同工酶抑制剂的体外效力相关联，以验证不同同工酶的相对重要性。
通过膀胱测压评估静脉注射几种非选择性和选择性COX - 2抑制剂（吲哚美辛、美洛昔康、萘普生、阿司匹林、对乙酰氨基酚、氟比洛芬、尼美舒利、NS - 398、塞来昔布、罗非昔布和L 745337）对清醒和麻醉大鼠膀胱充盈和排尿的影响。膀胱测压在清醒大鼠中于导管植入后1天进行，用稀醋酸（0.2%）或生理盐水充盈膀胱，在插管后5天再次用生理盐水充盈膀胱。还评估了对麻醉大鼠等容膀胱收缩的影响。
所有测试的NSAIDs均剂量依赖性地增加BVC；在膀胱用醋酸灌注期间增加BVC的效力与导管插入后1天膀胱测压用生理盐水评估的效力相似。当在插管后5天膀胱灌注生理盐水的大鼠中测试非选择性（萘普生）和选择性（尼美舒利）COX - 2抑制剂时，它们对BVC的影响明显低于1天时评估的结果。所有测试化合物均剂量依赖性地抑制麻醉大鼠的等容膀胱收缩。在麻醉大鼠中抑制等容膀胱收缩的效力与在清醒大鼠膀胱灌注醋酸期间膀胱测压增加BVC的效力之间存在良好的相关性。在膀胱灌注醋酸的膀胱测压模型和等容膀胱排尿收缩中，化合物的效力与COX - 2抑制密切相关，但与COX - 1无关。
非选择性和COX - 2选择性抑制剂在抑制由膀胱刺激引起膀胱过度活动的大鼠排尿反射方面比在正常大鼠中更具活性。抗炎化合物在抑制化学或手术刺激诱导的膀胱过度活动方面的效力，以及它们在几乎与膀胱刺激无关的膀胱测压模型（麻醉大鼠的等容膀胱收缩）中的活性，与作为COX - 2同工酶抑制剂的效力相关。这表明前列腺素在大鼠排尿反射中的参与主要由该同工酶介导。
