TRPV4 blockade reduces voiding frequency, ATP release and pelvic sensitivity in mice with chronic urothelial overexpression of NGF (NGF-OE).

Abstract

Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral DRG of transgenic mice with chronic, urothelial overexpression of NGF (NGF-OE) mice. We have evaluated the functional role of TRPV4 in bladder function with open outlet cystometry, void spot assays, and natural voiding assays (Urovoid) with a TRPV4 antagonist, HC067047 (1 μM) or vehicle in NGF-OE and littermate WT mice. Blockade of TRPV4 at the level of the urinary bladder significantly (p ≤ 0.01) increased intercontraction interval (ICI, 2.2-fold), void volume (VV, 2.6-fold) and decreased non-voiding contractions (3.0-fold) in NGF-OE mice with lesser effects in WT mice. Blockade of TRPV4 also increased ICI (1.3-fold) and VV (1.3-fold) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly (p ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly (p ≤ 0.01) reduced (2-fold) luminal ATP release from urinary bladder in NGF-OE and littermate WT mice. These studies suggest that TRPV4 contributes to luminal ATP release from the urinary bladder, increased voiding frequency and pelvic sensitivity in NGF-OE mice.