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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2009

Autores

Charrua A. (Autor) FCNAUP; Cruz C.D. (Autor) FMUP; Narayanan, S (Autor) Outra; Gharat, L (Autor) Outra; Gullapalli, S (Autor) Outra; Francisco Cruz (Autor) FMUP; António Avelino Silva (Autor) FMUP

Revista

Título: Journal of Urology

Vol. 181

Páginas: 379-386

ISSN: 0022-5347

Editora: Elsevier

Indexação

ISI Web of Knowledge - 78 Citações

Scopus - 93 Citações

Outras Informações

ID Authenticus: P-003-R4S

DOI: 10.1016/j.juro.2008.08.121

Abstract (EN): 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 <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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 8