PMID- 30580018
OWN - NLM
STAT- MEDLINE
DCOM- 20190301
LR  - 20190301
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 218
DP  - 2019 Feb 1
TI  - RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced 
      hyperactivity of the primary bladder afferent nerves in rats.
PG  - 89-95
LID - S0024-3205(18)30824-5 [pii]
LID - 10.1016/j.lfs.2018.12.031 [doi]
AB  - AIMS: To examine the effects of RQ-00434739, a novel selective TRPM8 antagonist, 
      on deep body temperature (DBT) and normal bladder sensory function and 
      overactivity and its associated facilitation of mechanosensitive primary bladder 
      single-unit afferent activities (SAAs) induced by intravesical l-menthol or 
      prostaglandin E2 (PGE2) instillation in rats. MAIN METHODS: The effect of 
      RQ-00434739 on DBT was evaluated using intravenous administration of RQ-00434739 
      (1 mg/kg) or its vehicle under urethane anaesthesia. Cystometry (CMG) was 
      performed on conscious and freely moving rats. SAAs were measured from the left 
      L6 dorsal root under urethane anaesthesia, and the fibers were grouped as Adelta- or 
      C-fiber based on their conduction velocity. For both CMG and SAA measurements, 
      after baseline recording with saline instillation, further recording was 
      performed with intravesical l-menthol (6 mM) or PGE2 (60 muM) instillation after 
      pretreatment with intravenous RQ-00434739 (1 mg/kg) or its vehicle. KEY FINDINGS: 
      RQ-00434739 did not significantly affect DBT. In CMG measurements, RQ-00434739 
      administration increased mean voided volume. Both l-menthol and PGE2 instillation 
      decreased mean voided volume following vehicle pretreatment, whereas such effects 
      were not observed following RQ-00434739 pretreatment. In SAA measurements, either 
      l-menthol or PGE2 instillations increased SAAs of C-fibers, but not SAAs of 
      Adelta-fibers, in the presence of vehicle. RQ-00434739 pretreatment significantly 
      inhibited the l-menthol- and PGE2-induced activation of C-fiber SAAs. 
      SIGNIFICANCE: The present results demonstrate that blockade of TRPM8 channels can 
      inhibit the pathological activation of mechanosensitive C-fibers and suggest that 
      RQ-00434739 may be a promising therapeutic drug candidate for bladder 
      hypersensitive disorders without affecting DBT.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Aizawa, Naoki
AU  - Aizawa N
AD  - Department of Continence Medicine, The University of Tokyo Graduate School of 
      Medicine, Tokyo, Japan. Electronic address: naizawa-nbs@umin.ac.jp.
FAU - Ohshiro, Hiroyuki
AU  - Ohshiro H
AD  - RaQualia Pharma Inc., Nagoya, Japan.
FAU - Watanabe, Shuzo
AU  - Watanabe S
AD  - RaQualia Pharma Inc., Nagoya, Japan.
FAU - Kume, Haruki
AU  - Kume H
AD  - Department of Urology, The University of Tokyo Graduate School of Medicine, 
      Tokyo, Japan.
FAU - Homma, Yukio
AU  - Homma Y
AD  - Department of Urology, The University of Tokyo Graduate School of Medicine, 
      Tokyo, Japan; Japanese Red Cross Medical Center, Tokyo, Japan.
FAU - Igawa, Yasuhiko
AU  - Igawa Y
AD  - Department of Continence Medicine, The University of Tokyo Graduate School of 
      Medicine, Tokyo, Japan.
LA  - eng
PT  - Journal Article
DEP - 20181220
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Oxytocics)
RN  - 0 (TRPM Cation Channels)
RN  - 0 (Trpm8 protein, rat)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Afferent Pathways/*drug effects
MH  - Animals
MH  - Body Temperature Regulation/*drug effects
MH  - Cells, Cultured
MH  - Dinoprostone/*toxicity
MH  - Male
MH  - Neurons, Afferent/*drug effects/metabolism/pathology
MH  - Oxytocics/toxicity
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - TRPM Cation Channels/*antagonists & inhibitors
MH  - Urinary Bladder/*drug effects/innervation/metabolism
MH  - Urinary Bladder Diseases/chemically induced/metabolism/*prevention & control
OTO - NOTNLM
OT  - Afferent
OT  - Prostaglandin E
OT  - Sprague-Dawley rats
OT  - TRPM cation channels
OT  - Urinary bladder diseases
EDAT- 2018/12/24 06:00
MHDA- 2019/03/02 06:00
CRDT- 2018/12/24 06:00
PHST- 2018/10/10 00:00 [received]
PHST- 2018/12/12 00:00 [revised]
PHST- 2018/12/18 00:00 [accepted]
PHST- 2018/12/24 06:00 [pubmed]
PHST- 2019/03/02 06:00 [medline]
PHST- 2018/12/24 06:00 [entrez]
AID - S0024-3205(18)30824-5 [pii]
AID - 10.1016/j.lfs.2018.12.031 [doi]
PST - ppublish
SO  - Life Sci. 2019 Feb 1;218:89-95. doi: 10.1016/j.lfs.2018.12.031. Epub 2018 Dec 20.