GRC - 6211是一种新型口服特异性瞬时受体电位香草酸亚型1（TRPV1）拮抗剂，可降低膀胱炎动物模型中的膀胱过度活动和有害膀胱传入。

GRC-6211, a new oral specific TRPV1 antagonist, decreases bladder overactivity and noxious bladder input in cystitis animal models.

作者信息

Charrua Ana, Cruz Célia D, Narayanan Shridhar, Gharat Laxmikant, Gullapalli Srinivas, Cruz Francisco, Avelino António

机构信息

Universidade do Porto, Porto, Portugal.

出版信息

J Urol. 2009 Jan;181(1):379-86. doi: 10.1016/j.juro.2008.08.121. Epub 2008 Nov 17.

DOI:10.1016/j.juro.2008.08.121

PMID:19010489

Abstract

PURPOSE

We evaluated the effects of GRC-6211, an orally active TRPV1 antagonist, on the function and noxious input of naïve and inflamed bladders.

MATERIALS AND METHODS

In urethane (Sigma(R)) anesthetized rats 0.5 ml 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 microM 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 naïve bladders was unchanged by GRC-6211 up to a dose of 0.1 mg/kg. At 1 mg/kg contractions were transiently suppressed in naïve 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 <0.05), 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 <0.05). GRC-6211 did not change bladder TRPV1 immunoreactivity.

CONCLUSIONS

GRC-6211 counteracts the bladder hyperactivity and noxious input induced by cystitis. At high doses it suppresses normal bladder activity by a TRPV1 dependent mechanism. TRPV1 antagonists might be useful for cystitis.

摘要

目的

我们评估了口服活性TRPV1拮抗剂GRC - 6211对未受损和发炎膀胱的功能及伤害性传入的影响。

材料与方法

在氨基甲酸乙酯（西格玛公司）麻醉的大鼠中，通过十二指肠导管给予0.5毫升GRC - 6211（0.001、0.01、0.1和1毫克/千克体重）或其赋形剂（0.5%甲基纤维素），并在输注生理盐水、100微摩尔辣椒素或0.5%乙酸（默克公司，英国费尔瑟姆）期间进行膀胱测压。也对用1毫克/千克GRC - 6211处理的野生型和TRPV1基因敲除小鼠进行了膀胱测压。在用0.1毫克/千克GRC - 6221或赋形剂处理后，对用脂多糖诱发炎症的大鼠进行膀胱测压。在给予0.1毫克/千克GRC - 6211或赋形剂后，研究0.5%乙酸诱导的脊髓c - fos表达。在给予GRC - 6211后评估膀胱中的TRPV1免疫反应性。

结果

高达0.1毫克/千克剂量的GRC - 6211对未受损大鼠和野生型小鼠膀胱的反射活动没有影响。在未受损大鼠和野生型小鼠中，1毫克/千克剂量时收缩被短暂抑制，但在TRPV1基因敲除小鼠中未出现这种情况。GRC - 6211（0.1毫克/千克）完全阻止了辣椒素诱导的刺激，而0.001、0.01或0.1毫克/千克剂量使乙酸输注期间膀胱收缩的平均±标准差频率分别从1.5±0.3降至1.35±0.35（无显著差异）、0.9±0.2（p<0.05）和0.8±0.2（p<0.05）。脂多糖诱发炎症的大鼠在给予赋形剂和GRC - 6211后，每分钟的收缩次数分别为1.4±0.4和0.8±0.1（p<0.05）。GRC - 6211使乙酸诱导的c - fos表达降低（从85.5±19.1降至46.7±9.4，p<0.05）。GRC - 6211未改变膀胱TRPV1免疫反应性。