Ca2+ Sparks and Urinary Bladder Smooth Muscle Excitability

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DESCRIPTION (provided by applicant): A number of diseases and pathologies are associated with both urinary incontinence and erectile dysfunction (ED), including diabetes, benign prostate hyperplasia, hypertension, and hyperlipidemia. The co-occurrence of urinary bladder and erectile dysfunction suggests the existence of mechanistic commonalities. One such point of convergence is the large conductance Ca2+-activated K+ (BK) channel, as evidenced by the fact that targeted disruption of the pore-forming BKa-subunit leads to overactive detrusor, urinary incontinence, and ED. A second potential common denominator is the NO/cGMP/PKG pathway, which regulates BK channel function directly as well as indirectly through calcium signaling elements that modulate BK channel function. The NO/cGMP/PKG pathway is nearly universally associated with smooth muscle (SM) relaxation. Yet, in contrast to corpus cavernosum (CC) SM, where nitrergic signaling through the PKG pathway is a well-established mediator of SM relaxation and erectile function, the role of NO in urinary bladder (UB) SM is an unsettled issue. In Aim 1, UBSM and CCSM will be investigated at the molecular and cellular levels to establish the potential of NO/cGMP/PKG signaling to regulate SM function, with an emphasis on the role of the BK channel pathway. BK channel function and PKG regulatory mechanisms in intact bladder and corpus tissue will be addressed in Aim 2, which will also consider the role of the cGMP-specific phosphodiesterase, PDE5, and Ca2+-sensitive chloride currents (ClCa) as potential contributors to tissue-specific differences in NO sensitivity. Finally, Aim 3 seeks to integrate the findings of Aim 1 and 2 and address the roles of the BK channel and cGMP/PKG pathways in regulating function during bladder filling using an ex vivo whole bladder model. Additionally, the role of these pathways in regulating intracavernous pressure and urodynamic properties during bladder filling will be addressed in vivo.The clinical success of the cGMP-specific phosphodiesterase-5 (PDE5) inhibitor sildenafil (Viagra) and related compounds in treating erectile dysfunction demonstrates a clear role for the cGMP-dependent protein kinase (PKG) pathway in regulating corpus cavernosum smooth muscle relaxation and erectile function. Despite the existence of both neuronal and urothelial sources of NO in the urinary bladder, and evidence for the expression of NO-responsive cGMP/PKG signaling pathway components in myocytes, the significance of the cGMP/PKG pathway in bladder physiology remains an unsettled question. The large conductance, calcium activated potassium (BK) channel, which has a central role in relaxing smooth muscle in the lower urinary tract, is a target of the PKG pathway, and represents a promising therapeutic target in the treatment of sildenafil-resistant ED and urinary incontinence.