Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis.
Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4(-/-) mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4(-/-) mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction.
Laboratory of Ion Channel Research, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Wouter
W
Everaerts
Xiaoguang
X
Zhen
Debapriya
D
Ghosh
Joris
J
Vriens
Thomas
T
Gevaert
James P
JP
Gilbert
Neil J
NJ
Hayward
Colleen R
CR
McNamara
Fenqin
F
Xue
Magdalene M
MM
Moran
Timothy
T
Strassmaier
Eda
E
Uykal
Grzegorz
G
Owsianik
Rudi
R
Vennekens
Dirk
D
De Ridder
Bernd
B
Nilius
Christopher M
CM
Fanger
Thomas
T
Voets
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000494:pharmacology; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000494:pharmacology; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism / Q000503:physiopathology*; D014554:Urination / Q000187:drug effects; D019459:Urothelium / Q000378:metabolism / Q000503:physiopathology*
D018906:Antineoplastic Agents, Alkylating; C573308:HC-067047; D049990:Membrane Transport Modulators; D009025:Morpholines; D011758:Pyrroles; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C486577:Trpv4 protein, rat; D003520:Cyclophosphamide