Pharmacological Separation of Mechanosensory Mechanisms in Rat Urinary Bladder Ex Vivo

The local response of the bladder wall to stretch is believed to result from the coordinated activation of mechanosensitive ion channels located in the plasma membrane of the cells that form the wall's urothelial and detrusor smooth muscle (DSM) layers. While the neuronal bladder control is well defined, the data on the mechanisms of local mechanical sensitivity of the bladder wall are either insufficient or contradictory. The involvement of mechanosensitive ion channels, TREK1, TRPV4, and PIEZO1, in determining stretch-dependent properties of the rat bladder wall was assessed by tensiometric measurements of stress-strain dependencies of mucosa-intact and mucosa-devoid DSM strips combined with channel-specific pharmacology. Here we show that TREK1, TRPV4, and PIEZO1 are functionally expressed in the rat bladder DSM and urothelium. TREK1 is coupled with bladder wall relaxation via decreasing DSM excitability and releasing of relaxant mediator(s) from the urothelium. TRPV4 in DSM is involved in gradually developing DSM tone during TREK1-dependent relaxation. Urothelial TRPV4 plays a role in the urothelium-mediated conversion of mechanical stretch into non-voiding spontaneous DSM contractions. DSM-localized PIEZO1 exhibits a higher sensitivity to stretching than TRPV4. Activation of urothelial PIEZO1 leads to the release of the mediator(s) with contractile action on DSM to limit the extent of bladder distention during filling. Our data distinguish the functional involvement of TREK1, TRPV4, and PIEZO1 in the autonomous mechanosensory properties of decentralized urinary bladder wall and provide a strategy for specific pharmacological targeting of bladder contraction/relaxation during different phases of bladder function.