AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome.
The activation of the TRPM8 channel, a member of the large class of TRP ion channels, has been reported to be involved in overactive bladder and painful bladder syndrome, although an endogenous activator has not been identified. In this study, N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride salt (AMTB) was evaluated as a TRPM8 channel blocker and used as a tool to evaluate the effects of this class of ion channel blocker on volume-induced bladder contraction and nociceptive reflex responses to noxious bladder distension in the rat. AMTB inhibits icilin-induced TRPM8 channel activation as measured in a Ca(2+) influx assay, with a pIC(50) of 6.23. In the anesthetized rat, intravenous administration of AMTB (3 mg/kg) decreased the frequency of volume-induced bladder contractions, without reducing the amplitude of contraction. The nociceptive response was measured by analyzing both visceromotor reflex (VMR) and cardiovascular (pressor) responses to urinary bladder distension (UBD) under 1% isoflurane. AMTB (10 mg/kg) significantly attenuated reflex responses to noxious UBD to 5.42 and 56.51% of the maximal VMR response and pressor response, respectively. The ID50 value on VMR response was 2.42 +/- 0.46 mg/kg. These results demonstrate that TRPM8 channel blocker can act on the bladder afferent pathway to attenuate the bladder micturition reflex and nociceptive reflex responses in the rat. Targeting TRPM8 channel may provide a new therapeutic opportunity for overactive bladder and painful bladder syndrome.
GlaxoSmithKline Pharmaceuticals, Department of Urology, 709 Swedeland Road, King of Prussia, PA 19406-0939, USA.
Erin S R
ES
Lashinger
Matthew S
MS
Steiginga
J Paul
JP
Hieble
Lisa A
LA
Leon
Scott D
SD
Gardner
Rakesh
R
Nagilla
Elizabeth A
EA
Davenport
Bryan E
BE
Hoffman
Nicholas J
NJ
Laping
Xin
X
Su
D000344:Afferent Pathways / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D009119:Muscle Contraction / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D011311:Pressoreceptors / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D053201:Urinary Bladder, Overactive / Q000378:metabolism*
D001549:Benzamides; C532415:N-(3-aminopropyl)-2-(((3-methylphenyl) methyl)oxy)-N-(2-thienylmethyl)benzamide hydrochloride salt; D050053:TRPM Cation Channels; D013876:Thiophenes; C498947:Trpm8 protein, rat