Tadalafil attenuates hypotonicity‐induced Ca²⁺ influx via TRPV2 and TRPV4 in primary rat bladder urothelial cell cultures

Abstract

Tadalafil attenuates Ca influx via TRPV4 and TRPV2, and inhibits ATP release in the bladder urothelium. These findings indicate that tadalafil functions as an inhibitor of urothelial signal transduction.

Phosphodiesterase-5 inhibition inhibits epithelial ATP release and restores detrusor contractility in rats with type 2 diabetesviaan increase in bladder blood flow

“…Although the nitric oxide (NO)/cyclic guanosine monophosphate (GMP) pathway is an endothelium-derived signal that induces vascular smooth muscle relaxation, the results of two previous studies suggest that it is also involved in bladder relaxation [39,40]. Another PDE5 inhibitor, sildenafil, has been shown to increase the cGMP concentration and inhibit the distention-induced release of ATP from the bladder epithelium in mice [39], and to significantly reduce the amount of ATP released in response to lipopolysaccharide administration.…”

“…A possible mechanism by which PDE5 inhibition reduces the release of ATP is the attenuation of the Ca 2+ influx via transient receptor potential vanilloid (TRPV) 2 and 4 [40]. In the present study, 12 weeks of tadalafil administration markedly reduced ATP release from the bladder epithelium, but it is unclear whether this was an acute effect, exerted via the NO-cGMP pathway, or a chronic effect, associated with lower proinflammatory cytokine production, secondary to an improvement in blood flow.…”

Purinergic signalling in the urinary bladder – When function becomes dysfunction

“…Basal and stretch-activated ATP release through TRPV4 channels has also been demonstrated (Mochizuki et al, 2009;Everaerts et al, 2010;Girard et al, 2019;Roberts et al, 2020), consistent with impaired voiding function when TRPV4 channels were knocked out (Gevaert et al, 2007). Agents that limit Ca 2+ influx through TRPV4 and TRPV2 channels, such as the phosphodiesterase-5 inhibitor, tadalafil, also attenuate stretch-induced ATP release (Dong et al, 2018) and the potential use of TRP channel modulators to manage overactive bladder symptoms has been recently discussed (Fry et al, 2020). The role of ENaC modulators has been less well characterised.…”