Age‐related changes in afferent pathways and urothelial function in the male mouse bladder

Abstract

The prevalence of lower urinary tract storage disorders such as overactive bladder syndrome and urinary incontinence significantly increase with age. Previous studies have demonstrated age-related changes in detrusor function and urothelial transmitter release but few studies have investigated how the urothelium and sensory pathways are affected. The aim of this study was to investigate the effect of ageing on urothelial-afferent signalling in the mouse bladder. Three-month-old control and 24-month-old aged male mice were used. In vivo natural voiding behaviour, sensory nerve activity, urothelial cell function, muscle contractility, transmitter release and gene and protein expression were measured to identify how all three components of the bladder (neural, contractile and urothelial) are affected by ageing. In aged mice, increased voiding frequency and enhanced low threshold afferent nerve activity was observed, suggesting that ageing induces overactivity and hypersensitivity of the bladder. These changes were concurrent with altered ATP and acetylcholine bioavailability, measured as transmitter overflow into the lumen, increased purinergic receptor sensitivity and raised P2X3 receptor expression in the urothelium. Taken together, these data suggest that ageing results in aberrant urothelial function, increased afferent mechanosensitivity, increased smooth muscle contractility, and changes in gene and protein expression (including of P2X3). These data are consistent with the hypothesis that ageing evokes changes in purinergic signalling from the bladder, and further studies are now required to fully validate this idea.

Purinergic signalling during development and ageing

“…The response of the bladder to α,β-meATP increased with age [351], but P2X1 and P2X3 receptor mRNA did not change with age. In aged male mice, there was an increase in bladder voiding, augmented P2X3 receptor-mediated afferent nerve firing during bladder filling and an increase in urothelial activation by ATP [352]. The authors speculated that this may reflect the increase in overactive bladder in ageing humans.…”

Purinergic signalling in the urinary bladder

“…In the mouse bladder, Daly et al (2014) found altered ATP and ACh bioavailability, increased purinergic receptor sensitivity and raised P2X 3 receptor expression in the urothelium. Sui et al (2014a,b) measured intrinsic ATP release in mucosal preparations from aged guinea pigs.…”

The purinergic neurotransmitter revisited: A single substance or multiple players?

“…P2X3 receptor knockout mice had marked urinary bladder hyporeflexia with reduced voiding frequency and increased voiding volume, suggesting that these receptors are involved in mechanosensory transduction underlying activation of afferent fibers that control voiding reflexes during bladder filling (Cockayne et al, 2000). Age-related changes in afferent pathways were demonstrated in male mouse bladder (Daly et al, 2014): bladders from aged mice showed increased voiding frequency and enhanced low-threshold afferent nerve activity concurrent with increased purinergic receptor sensitivity and raised P2X3 receptor expression in the urothelium and increased levels ATP, but decreased levels of acetylcholine in the bladder lumen. Increased stretch-activated ATP release from bladder urothelium was demonstrated in patients with interstitial cystitis (Sun et al, 2001), painful bladder syndrome (Kumar et al, 2007), and idiopathic detrusor overactivity (Kumar et al, 2010).…”