Table 2.
Effects of GSK1016790A on voiding frequency and VV are reversed by HC-067047 in WT and NGF-OE mice
| Experimental Groups | VV, µL | ICI, s |
|---|---|---|
| WT + vehicle | 122.4 ± 10.3 | 262.4 ± 8.5 |
| WT + GSK1016790A (100 nM) | 59.4 ± 9.5* | 125.4 ± 4.7* |
| WT + GSK1016790A + HC-067047 (1 µM) | 112.5 ± 8.7* | 253.6 ± 4.5* |
| NGF-OE + vehicle | 52.2 ± 6.2 | 97.6 ± 10.2 |
| NGF-OE + GSK1016790A (100 nM) | 24.4 ± 5.6* | 48.5. ± 9.4* |
| NGF-OE + GSK1016790A + HC-067047 (1 µM) | 45.5 ± 3.5* | 101.7 ± 11.8* |
| TRPV4−/− + vehicle | 215.8 ± 18.9* | 381.7 ± 35.0* |
| TRPV4−/− + GSK1016790A (100 nM) | 219.2 ± 17.8* | 390.4 ± 22.6* |
| TRPV4−/− + GSK1016790A + HC-067047 (1 µM) | 224.1 ± 11.2* | 393.3 ± 33.2* |
Values are means ± SE; n = 6 for each group. In control, conscious cystometry experiments with continuous infusion and an open outlet, effects of intravesical instillation of the transient receptor potential vanilloid family member 4 (TRPV4) agonist GSK1016790A (100 nM) were evaluated in wild-type (WT; n = 6) and transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE; n = 6) followed by intravesical instillation of the TRPV4 antagonist HC-067047 (1 µM). GSK1016790A (100 nM) significantly decreased intercontraction interval [ICI (voiding frequency)] and void volume (VV) in WT and NGF-OE mice compared with vehicle treatment. Increased voiding frequency and reduced VV were reversed in WT and NGF-OE mice with intravesical instillation of HC-067047 (1 µM). Intravesical infusion of GSK1016790A (100 nM) followed by intravesical infusion of HC-067047 (1 µM) significantly increased VV and ICI compared with GSK1016790A alone. Effects of intravesical instillation of GSK1016790A (100 nM) followed by intravesical instillation of HC-067047 (1 µM) were also evaluated in TRPV4−/−mice (n = 6). GSK1016790A (100 nM) had no effect on ICI or VV in TRPV4−/− mice compared with vehicle. Subsequent intravesical infusion of HC-067047 (1 µM) was also without effect on VV and ICI compared with GSK1016790A alone or vehicle. VV and ICI were significantly greater for vehicle-, TRPV4 agonist-, or TRPV4 antagonist-treated TRPV4−/− mice than for WT or NGF-OE mice with vehicle or drug treatment.
P ≤ 0.01.