Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats
Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats
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DOI：
10.1111/j.1464-410x.2007.07310.x
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发表时间：
2008-03-01
影响因子：
4.5
通讯作者：
Yoshimura, Naoki
中科院分区：
文献类型：
--
作者：
Masuda, Hitoshi;Kihara, Kazunori;Yoshimura, Naoki
研究活性氧（ROS）对体内排尿反射的影响，特别是对大鼠膀胱传入信号的影响，因为膀胱的几种病理生理状况（如缺血/再灌注和炎症）都以ROS的形成为特征。用连续膀胱造影（CMG）评估聚氨酯麻醉下成年雌性Sprague-Dawley大鼠（正常或预处理，4天前皮下注射125 mg/kg辣椒素），同时或不同时膀胱内注射H2O2（0.003-3%）刺激ROS损伤。为了研究H2O2的作用机制，采用过氧化氢酶（H2O2清除剂）静脉注射（2000 IU/mL）或大鼠静脉注射超氧化物歧化酶（SOD, 20 000 IU/kg，一种超氧阴离子清除剂）、二甲基硫脲（DMTU, 100 mg/kg，一种羟基自由基清除剂）、去铁胺（20 mg/kg，一种阻止羟基自由基形成的铁螯合剂）、吲哚美辛（3 mg/kg，一种环氧化酶抑制剂）或酮洛芬(1 mg/kg，一种环加氧酶抑制剂)，在体内给H2O2之前或期间。在不加或不加吲哚美辛的情况下，膀胱内灌注0.3% H2O2 30 min，测定膀胱内前列腺素（PG）水平(PGE（2)和6-酮- pgf (1 α)）。正常大鼠膀胱内给予H2O2诱导逼尿肌过度活动，如平均收缩间期（ICI）的减少所示，呈剂量依赖性（0.3% H2O2, P < 0.01，对照组ICI的36.2(4.7)%）。过氧化氢酶几乎能消除h2o2诱导的逼尿肌过度活动，DMTU、去铁胺、辣椒素预处理、吲哚美辛和酮洛芬均能显著抑制逼尿肌过度活动，SOD则不能。H2O2灌胃能显著提高PGs水平，吲哚美辛能显著抑制PGs的升高。这些结果表明，H2O2诱导的氧化应激激活辣椒素敏感的c纤维传入途径，至少部分通过刺激环加氧酶途径介导，从而诱导逼尿肌过度活跃。因此，用膀胱内H2O2处理的大鼠似乎是研究逼尿肌过度活动的合适模型。
To investigate the effects of reactive oxygen species (ROS) on the micturition reflex in vivo, especially in bladder afferent signalling in rats, as several pathophysiological conditions in the urinary bladder (e.g. ischaemia/reperfusion and inflammation) are characterized by the formation of ROS.Adult female Sprague-Dawley rats under urethane anaesthesia (normal or pretreated with 125 mg/kg capsaicin, subcutaneously, 4 days before) were assessed by continuous cystometrography (CMG) with or without the intravesical administration of H2O2 (0.003-3%) to stimulate ROS damage. To investigate the mechanism of H2O2, catalase (a H2O2 scavenger) was applied intravesically (2000 IU/mL), or rats were given intravenous injections with superoxide dismutase (SOD, 20 000 IU/kg, a superoxide anion scavenger), dimethylthiourea (DMTU, 100 mg/kg, a hydroxyl radical scavenger), deferoxamine (20 mg/kg, an iron-chelator that prevents the formation of hydroxyl radical), indomethacin (3 mg/kg, a cyclooxygenase inhibitor) or ketoprofen (1 mg/kg, a cyclooxygenase inhibitor) just before or during the intravesical administration of H2O2. Prostaglandin (PG) levels (PGE(2) and 6-keto-PGF(1 alpha)) were measured in the bladder of rats treated with intravesical 0.3% H2O2 for 30 min with or without indomethacin.Intravesical administration of H2O2 induced detrusor overactivity, as shown by a reduction in the mean intercontraction interval (ICI), in a dose-dependent manner in normal rats (0.3% H2O2, P < 0.01, 36.2 (4.7)% of the control ICI). H2O2-induced detrusor overactivity was almost abolished by catalase and significantly suppressed by DMTU, deferoxamine, capsaicin pretreatment, indomethacin or ketoprofen but not by SOD. The level of PGs was significantly increased by H2O2 instillation, and indomethacin significantly inhibited the increase in PGs.These results indicate that oxidative stress induced by H2O2 activates capsaicin-sensitive C-fibre afferent pathways, at least in part, mediated via stimulation of the cyclooxygenase pathway, thereby inducing detrusor overactivity. Thus, rats treated with intravesical H2O2 appear to be a suitable model for the study of detrusor overactivity.