GRC-6211, a New Oral Specific TRPV1 Antagonist, Decreases Bladder Overactivity and Noxious Bladder Input in Cystitis Animal Models
GRC-6211, a New Oral Specific TRPV1 Antagonist, Decreases Bladder Overactivity and Noxious Bladder Input in Cystitis Animal Models
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DOI：
10.1016/j.juro.2008.08.121
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发表时间：
2009-01-01
影响因子：
6.6
通讯作者：
Avelino, Antonio
中科院分区：
文献类型：
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作者：
Charrua, Ana;Cruz, Celia D.;Avelino, Antonio
目的：我们评估了口服活性TRPV 1拮抗剂GRC-6211对幼稚和炎症膀胱的功能和伤害性输入的影响。材料和方法：在乌拉坦（Sigma（R））麻醉大鼠0.5卷GRC-6211（0.001、0.01、0.1和1 mg/kg体重）或其溶媒（0.5%甲基纤维素）通过十二指肠导管给药，并在输注盐水、100 μ M辣椒素或0.5%乙酸期间进行膀胱测压（Merck，费尔瑟姆，联合王国）。还在用1 mg/kg GRC-6211处理的WT和TRPV 1敲除小鼠中进行膀胱测量。在接受0.1 mg/kg GRC-6221或溶媒后，对脂多糖致炎大鼠进行膀胱测量。在0.1 mg/kg GRC-6211或溶剂给药后，研究了0.5%乙酸诱导的脊髓c-fos表达。结果：大鼠和野生型小鼠膀胱的反射活动在0.1 mg/kg剂量的GRC-6211下无明显变化。在1 mg/kg剂量下，未处理大鼠和WT小鼠的收缩受到短暂抑制，但TRPV 1敲除小鼠未受到抑制。GRC-6211 0.001、0.01或0.1 mg/kg剂量将乙酸输注期间膀胱收缩的平均+/- SD频率从1.5 +/- 0.3降低至1.35 +/- 0.35 05）和0.8 +/-0.2（p < 10.05）。脂多糖发炎的大鼠在媒介物和GRC-6211后分别具有1.4 +/-0.4和0.8 +/-0.1次收缩/分钟（p < 0.05）。GRC-6211可降低乙酸诱导的c-fos表达（85.5 ± 19.1至46.7 ± 9.4，p
Purpose: We evaluated the effects of GRC-6211, an orally active TRPV1 antagonist, on the function and noxious input of naive and inflamed bladders.Materials and Methods: In urethane (Sigma (R)) anesthetized rats 0.5 roll GRC-6211 (0.001, 0.01, 0.1 and 1 mg/kg weight) or its vehicle (0.5% methylcellulose) were administered through a duodenal catheter and cystometry was done during infusion of saline, 100 mu M capsaicin or 0.5% acetic acid (Merck, Feltham, United Kingdom). Cystometry was also performed in WT and TRPV1 knockout mice treated with 1 mg/kg GRC-6211. Cystometry was done in rats inflamed with lipopolysaccharide after receiving 0.1 mg/kg GRC-6221 or vehicle. Spinal c-fos expression induced by 0.5% acetic acid was investigated after 0.1 mg/kg GRC-6211 or vehicle administration. TRPV1 immunoreactivity was evaluated in the bladder after GRC-6211 administration.Results: The reflex activity of rat and WT mice naive bladders was unchanged by GRC-6211 up to a dose of 0.1 mg/kg. At 1 mg/kg contractions were transiently suppressed in naive rats and WT mice but not in TRPV1 knockout mice. GRC-6211 (0.1 mg/kg) completely prevented capsaicin induced irritation, while the 0.001, 0.01 or 0.1 mg/kg dose decreased the mean +/- SD frequency of bladder contractions during acetic acid infusion from 1.5 +/- 0.3 to 1.35 +/- 0.35 (not significant), 0.9 +/- 0.2 (p < 0.05) and 0.8 +/- 0.2 (p < 10.05), respectively. Lipopolysaccharide inflamed rats had 1.4 +/- 0.4 and 0.8 +/- 0.1 contractions per minute after vehicle and GRC-6211, respectively (p < 0.05). The c-fos expression induced by acetic acid was decreased by GRC-6211 (85.5 +/- 19.1 to 46.7 +/- 9.4, p