DFL23448, a novel TRPM8-selective ion channel antagonist, modifies bladder function and reduces bladder overactivity in awake rats.
Författare
Summary, in English
The transient receptor potential (TRP) melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity (BO) is available. This study characterizes a new TRPM8-selective antagonist (DFL23448) and evaluates it in cold-induced behavioral tests and on bladder function and experimental BO in vivo in rats. DFL23448 displayed IC50 values of 10 and 21nM in hTRPM8 HEK-293 cells activated by Cooling Agent 10 or cold, but had limited activity (IC50 > 10μM) at TRPV1, TRPA1, TRPV4, or at various G-protein-coupled receptors. In rats, DFL23448 had a half-life of 37 minutes (intravenous; i.v.) or 4.9 hours (oral). DLF23448 (10mg/kg, i.v) reduced icilin-induced wet-dog shakes in rats. Intravesical (i.ves.) DFL23448 (10mg/L) but not vehicle increased micturition intervals (MI), micturition volumes (MV) and bladder capacity (BC). During BO by i.ves. PGE2, vehicle controls exhibited reductions of MI, MV and BC by 37-39%, whereas the same parameters only decreased by 12-15% (p<0.05-0.01 vs. vehicle) in DFL23448-treated rats. In vehicle-treated rats but not in DFL23448-treated rats, i.ves. PGE2 increased bladder pressures. Intravenous DFL23448 at 10mg/kg, but not 1mg/kg DFL23448 or vehicle, increased MI, MV, and BC. During BO by i.ves. PGE2, MI, MV, and BC decreased in vehicle- and in DFL23448 1mg/kg-treated rats, but not in DFL23448 10mg/kg-treated rats. Bladder pressures increased less in rats treated with DFL23448 10mg/kg than in vehicle- or DFL23448 1mg/kg- treated rats. DFL23448 (10mg/kg, i.v.), but not vehicle, prevented cold-stress BO. Our results support a role for bladder TRPM8-mediated signals in experimental BO.
Avdelning/ar
Publiceringsår
2016
Språk
Engelska
Sidor
200-211
Publikation/Tidskrift/Serie
Journal of Pharmacology and Experimental Therapeutics
Volym
356
Issue
1
Dokumenttyp
Artikel i tidskrift
Förlag
American Society for Pharmacology and Experimental Therapeutics
Ämne
- Pharmacology and Toxicology
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1521-0103