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Research Article

Augmented Bladder Urothelial Polyamine Signaling and Block of BK-channel in the Pathophysiology of Overactive Bladder Syndrome

¹University of Maryland School of Medicine ²University of Maryland

Submitted 16 June 2009 ; revised 28 September 2009 ; accepted in final form 28 September 2009

Overactive bladder syndrome (OAB) is an idiopathic condition characterized by urinary urgency and urge incontinence. Detrusor overactivity has been traditionally described as the physiologic mechanism for OAB. However, the bladder urothelium (BU) may also be involved in the pathophysiology. This study measured polyamine signaling and its downstream effects on membrane conductivity in bladder urothelial cells (BUC) obtained from asymptomatic and OAB subjects. Immunohistofluorescence was used to measure ornithine decarboxylase (ODC) expression in BU. BUC, cultured from BU biopsies, were used for electrophysiologic studies. D, L- -difluoromethyl ornithine (DFMO), spermine or spermidine were used to modulate polyamine signaling in BUC. Results showed ODC over-expression in OAB BU. In OAB BUC, whole cell and cell-attached configuration showed significantly decreased currents. Using inside-out patches, outward currents increased significantly suggesting a cytoplasmic source of the outward current block in OAB BUC. In control BUC, outward currents were mediated by the large conductance calcium-activated potassium channel (BK) due to calcium dose-dependence and block by iberiotoxin. Spermidine and spermine blocked the outward current in normal BUC in dose-dependent fashion. Conversely, DFMO significantly increased (p<0.01) outward currents in OAB BUC both in cell-attached and whole cell configuration. The outward currents in DFMO-treated-OAB BUC could be significantly reduced (p<0.05) by adding back spermidine and spermine. These data suggest that polyamine signaling is upregulated in OAB urothelium and OAB BUC. Furthermore, polyamines in BUC block the BK channel. Targeting of bladder urothelial polyamine signaling may represent a novel approach for OAB treatment based on pathophysiologic mechanisms.

overactive bladder; urothelial cell; polyamine; electrophysiology