GRC-6211, a New Oral Specific TRPV1 Antagonist, Decreases Bladder Overactivity and Noxious Bladder Input in Cystitis Animal Models

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®) 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 μM 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.

Key Words: urinary bladder, Trpv1 protein, rat, cystitis, inflammation, pain

Abbreviations and Acronyms: KO, knockout, LPS, lipopolysaccharide, TRPV1, transient receptor potential vanilloid subfamily 1