Nav1.9 regulates bladder capacity in cyclophosphamide‐induced overactive bladder

Abstract

We have recently confirmed Nav1.9 as the molecular entity underlying the persistent, tetrodotoxin-resistant, voltage-gated Na+ current in small diameter dorsal root ganglion neurons, and have demonstrated a functional role for Nav1.9 in the maintenance of inflammation-induced hyperalgesia (Priest et al. 2005). Here, utilizing Nav1.9 knock-out (KO) mice, we have investigated a potential role for Nav1.9 in the regulation of urinary bladder function. Cystometry was performed on awake, freely moving animals to evaluate urodynamic properties in Nav1.9 KO and wild-type (WT) littermate controls. Basal urodynamics, and the response to acetic acid induced overactive bladder, were not different between genotypes. Intravesicular infusion of acetic acid (0.25%) into the bladder resulted in a ~ 50% reduction in bladder capacity, an increased minimum filling pressure, and a reduction in micturition pressure threshold in both WT (n=7) and KO (n=7) mice. Cyclophosphamide, given IP at 150 mg/kg, evoked variable increases in bladder pressure in KO (n=6) and WT (n=7) mice, with no effect on bladder capacities at 24 hours. Increasing cyclophosphamide to 300 mg/kg reduced bladder capacity in WT (n=9), but had no effect in Nav1.9 KO mice (n=8). This differential reactivity of Nav1.9 KO mice in the acute, chemically-induced acetic acid overactivity model, versus the inflammatory-mediated cyclophosphamide model, is consistent with the known regulation of Nav1.9 channels by inflammatory mediators, such as prostaglandin E2.