PMID- 29464762
OWN - NLM
STAT- MEDLINE
DCOM- 20190930
LR  - 20190930
IS  - 1520-6777 (Electronic)
IS  - 0733-2467 (Linking)
VI  - 37
IP  - 5
DP  - 2018 Jun
TI  - KPR-2579, a novel TRPM8 antagonist, inhibits acetic acid-induced bladder afferent 
      hyperactivity in rats.
PG  - 1633-1640
LID - 10.1002/nau.23532 [doi]
AB  - AIMS: Transient receptor potential melastatin 8 (TRPM8) is proposed to be a 
      promising therapeutic target for hypersensitive bladder disorders. We examined 
      the effects of KPR-2579, a novel selective TRPM8 antagonist, on body temperature 
      and on mechanosensitive bladder single-unit afferent activities (SAAs) provoked 
      by intravesical acetic acid (AA) instillation in rats. METHODS: Female 
      Sprague-Dawley rats were used. Effects of cumulative intravenous (i.v.) 
      administrations of KPR-2579 (0.03-1 mg/kg) on deep body temperature were 
      investigated (N = 18). In separate animals, effects of bolus administration of 
      KPR-2579 (0.03 or 0.3 mg/kg, i.v.) on bladder hyperactivity induced by 
      intravesical instillation of 0.1% AA were investigated using cystometry (N = 57) 
      in a conscious free-moving condition or urethane-anesthetized condition, and SAA 
      measurements (N = 41) were performed in a urethane-anesthetized condition. 
      RESULTS: KPR-2579 at any doses tested did not affect body temperature. In 
      cystometry measurements, a high dose (0.3 mg/kg) of KPR-2579 counteracted the 
      shortened intercontraction interval provoked by AA instillation. In SAA 
      measurements, 48 single afferent fibers (n = 24 in each fiber) were isolated. AA 
      instillations significantly increased the SAAs of C fibers, but not of Adelta fibers, 
      in the presence of KPR-2579's vehicle and a low dose (0.03 mg/kg) of KPR-2579. 
      Pretreatment with a high dose (0.3 mg/kg) of KPR-2579 significantly inhibited the 
      AA-induced activation of C-fiber SAAs. CONCLUSION: The present results suggest 
      that TRPM8 channels play a role in the AA-induced pathological activation of 
      mechanosensitive bladder C fibers in rats. KRP-2579 may be a promising drug for 
      hypersensitive bladder disorders.
CI  - (c) 2018 Wiley Periodicals, Inc.
FAU - Aizawa, Naoki
AU  - Aizawa N
AUID- ORCID: 0000-0002-4645-9293
AD  - Department of Continence Medicine, The University of Tokyo Graduate School of 
      Medicine, Tokyo, Japan.
FAU - Fujimori, Yoshikazu
AU  - Fujimori Y
AD  - Discovery Research R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan.
FAU - Kobayashi, Jun-Ichi
AU  - Kobayashi JI
AD  - Discovery Research R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan.
FAU - Nakanishi, Osamu
AU  - Nakanishi O
AD  - Discovery Research R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan.
FAU - Hirasawa, Hideaki
AU  - Hirasawa H
AD  - Discovery Research R&D, Kissei Pharmaceutical Co., Ltd., Azumino, 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.
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
PT  - Research Support, Non-U.S. Gov't
DEP - 20180221
PL  - United States
TA  - Neurourol Urodyn
JT  - Neurourology and urodynamics
JID - 8303326
RN  - 0 (TRPM Cation Channels)
RN  - 0 (Trpm8 protein, rat)
RN  - Q40Q9N063P (Acetic Acid)
SB  - IM
MH  - Acetic Acid
MH  - Animals
MH  - Female
MH  - Nerve Fibers, Unmyelinated/*drug effects/physiology
MH  - Neurons, Afferent/physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - TRPM Cation Channels/*antagonists & inhibitors
MH  - Urinary Bladder, Overactive/chemically induced/*drug therapy
OTO - NOTNLM
OT  - Sprague-Dawley rats
OT  - TRPM cation channels
OT  - acetic acid
OT  - afferent
OT  - urinary bladder diseases
EDAT- 2018/02/22 06:00
MHDA- 2019/10/01 06:00
CRDT- 2018/02/22 06:00
PHST- 2017/12/27 00:00 [received]
PHST- 2018/01/27 00:00 [accepted]
PHST- 2018/02/22 06:00 [pubmed]
PHST- 2019/10/01 06:00 [medline]
PHST- 2018/02/22 06:00 [entrez]
AID - 10.1002/nau.23532 [doi]
PST - ppublish
SO  - Neurourol Urodyn. 2018 Jun;37(5):1633-1640. doi: 10.1002/nau.23532. Epub 2018 Feb 
      21.