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.
Everaerts
Wouter
W
Laboratory of Ion Channel Research, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Zhen
Xiaoguang
X
Ghosh
Debapriya
D
Vriens
Joris
J
Gevaert
Thomas
T
Gilbert
James P
JP
Hayward
Neil J
NJ
McNamara
Colleen R
CR
Xue
Fenqin
F
Moran
Magdalene M
MM
Strassmaier
Timothy
T
Uykal
Eda
E
Owsianik
Grzegorz
G
Vennekens
Rudi
R
De Ridder
Dirk
D
Nilius
Bernd
B
Fanger
Christopher M
CM
Voets
Thomas
T
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