Charrua Ana, Cruz Célia D, Narayanan Shridhar, Gharat Laxmikant, Gullapalli Srinivas, Cruz Francisco, Avelino António
Universidade do Porto, Porto, Portugal.
J Urol. 2009 Jan;181(1):379-86. doi: 10.1016/j.juro.2008.08.121. Epub 2008 Nov 17.
We evaluated the effects of GRC-6211, an orally active TRPV1 antagonist, on the function and noxious input of naïve and inflamed bladders.
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.
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.
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.
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。
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。
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。
GRC - 6211可对抗膀胱炎诱导的膀胱活动亢进和伤害性传入。高剂量时，它通过TRPV1依赖机制抑制正常膀胱活动。TRPV1拮抗剂可能对膀胱炎有用。
