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DFL23448, a novel T...
DFL23448, a novel TRPM8-selective ion channel antagonist, modifies bladder function and reduces bladder overactivity in awake rats.
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Mistretta, Francesco A (författare)
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Russo, Andrea (författare)
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Castiglione, Fabio (författare)
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Bettiga, Arianna (författare)
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Colciago, Giorgia (författare)
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Montorsi, Francesco (författare)
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Brandolini, Laura (författare)
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Aramini, Andrea (författare)
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Bianchini, Gianluca (författare)
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Allegretti, Marcello (författare)
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Bovolenta, Silvia (författare)
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Russo, Roberto (författare)
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Benigni, Fabio (författare)
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- Hedlund, Petter (författare)
- Linköping University,Lund University,Lunds universitet,Avdelningen för klinisk kemi och farmakologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Chemistry and Pharmacology,Department of Laboratory Medicine,Faculty of Medicine
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(creator_code:org_t)
- 2015-11-06
- 2016
- Engelska.
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103. ; 356:1, s. 200-211
- Relaterad länk:
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http://dx.doi.org/10...
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https://jpet.aspetjo...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
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Mistretta, Franc ...
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Russo, Andrea
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Castiglione, Fab ...
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Bettiga, Arianna
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Colciago, Giorgi ...
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Montorsi, France ...
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visa fler...
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Brandolini, Laur ...
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Aramini, Andrea
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Bianchini, Gianl ...
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Allegretti, Marc ...
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Bovolenta, Silvi ...
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Russo, Roberto
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Benigni, Fabio
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Hedlund, Petter
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visa färre...
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