Cells and ionic conductances contributing to spontaneous activity in bladder and urethral smooth muscle

Smooth muscle organs of the lower urinary tract comprise the bladder detrusor and urethral wall, which have a reciprocal contractile relationship during urine storage and micturition. As the bladder fills with urine, detrusor smooth muscle cells (DSMCs) remain relaxed to accommodate increases in intravesical pressure while urethral smooth muscle cells (USMCs) sustain tone to occlude the urethral orifice, preventing leakage. While neither organ displays coordinated regular contractions as occurs in small intestine, lymphatics or renal pelvis, they do exhibit patterns of rhythmicity at cellular and tissue levels. In rabbit and guinea-pig urethra, electrical slow waves are recorded from USMCs. This activity is linked to cells expressing vimentin, c-kit and Ca2+-activated Cl- channels, like interstitial cells of Cajal in the gastrointestinal tract. In mouse, USMCs are rhythmically active (firing propagating Ca2+ waves linked to contraction), and this cellular rhythmicity is asynchronous across tissues and summates to form tone. Experiments in mice have failed to demonstrate a voltage-dependent mechanism for regulating this rhythmicity or contractions in vitro, suggesting that urethral tone results from an intrinsic ability of USMCs to 'pace' their own Ca2+ mobilization pathways required for contraction. DSMCs exhibit spontaneous transient contractions, increases in intracellular Ca2+ and action potentials. Consistent across numerous species, including humans, this activity relies on voltage-dependent Ca2+ influx in DSMCs. While interstitial cells are present in the bladder, they do not 'pace' the organ in an excitatory manner. Instead, specialized cells (PDGFR alpha+ interstitial cells) may 'negatively pace' DSMCs to prevent bladder overexcitability. image figure legend Cells and conductances contributing to spontaneous activity in the lower urinary tract. Bladder and urethra exhibit spontaneous contractions at both cellular and tissue levels. Both detrusor and urethral smooth muscle cells display activity that is regular and rhythmic. Distinct populations of interstitial cells exist in muscle layers of both organs, with platelet derived growth factor receptor-alpha+ cells present in detrusor, and Kit+ cells (interstitial cell of Cajal-like cells) in urethra. These cells may influence activity of detrusor and urethral smooth muscle, respectively. Detrusor and urethral smooth muscle cells rely on varying complements of ion channels to regulate spontaneous activity. In bladder, small and large conductance potassium channels (SK3/BK) and voltage-dependent calcium channels (Cav1.2) are consistently found to be important. In urethra, there is disparity among species and investigators as to the importance of Cav1.2, calcium activated chloride (Ano1) channels and Orai calcium channels. This review summarizes the current thoughts of the field on these similarities and discrepancies. image