Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis

Abstract

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. transient receptor potential channels | urothelium

TRPV4 channels stimulate Ca 2 + -induced Ca 2+ release in astrocytic endfeet and amplify neurovascular coupling responses

“…1D), or in slices preincubated with the selective TRPV4 antagonist, HC-067047 (10 μM; n = 6 slices from four animals) ( Fig. 1E) (31). Whereas the increase in endfoot Ca 2+ oscillations to GSK was prevented by HC-067047, there was no apparent effect of HC-067047 on spontaneous endfoot Ca 2+ oscillation frequency (Control, n = 16; HC, n = 9) (Fig.…”

Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3

“…It is very important to investigate whether Pirt is involved in the modulation of bladder activity. Therefore, we examined the role of Pirt in mice treated with cyclophosphamide (CYP), which has been used as a chemical irritant (via conversion to acrolein) in models of bladder overactivity 1,18,19 . CYP was intraperitoneal administered at the first, the third and the fifth day individually.…”

Ion channel therapeutics for pain

“…9). These include RN-1734 33 from Renovis, Hydra's HC-067047; a compound reported to be efficacious in preclinical models of bladder cystitis, 34 and sulphonamide 25 from Pfizer. 35 To date, the only TRPV4 ligand to have entered clinical trials is GSK 2798745, a compound of undisclosed structure that has entered a Phase 1 study.…”