Abstract
Patients suffering from a variety of neurological diseases such as spinal cord injury, Parkinson’s disease, and multiple sclerosis often develop neurogenic detrusor overactivity (NDO), which currently lacks a universally effective therapy. Here, we tested the hypothesis that NDO is associated with changes in detrusor smooth muscle (DSM) large conductance Ca2+-activated K+ (BK) channel expression and function. DSM tissue samples from 33 patients were obtained during open bladder surgeries. NDO patients were clinically characterized preoperatively with pressure-flow urodynamics demonstrating detrusor overactivity, in the setting of a clinically relevant neurological condition. Control patients did not have overactive bladder and did not have a clinically relevant neurological disease. We conducted quantitative polymerase chain reactions (qPCR), perforated patch-clamp electrophysiology on freshly-isolated DSM cells, and functional studies on DSM contractility. qPCR experiments revealed that DSM samples from NDO patients showed decreased BK channel mRNA expression in comparison to controls. Patch-clamp experiments demonstrated reduced whole cell and transient BK currents (TBKCs) in freshly-isolated DSM cells from NDO patients. Functional studies on DSM contractility showed that spontaneous phasic contractions had a decreased sensitivity to iberiotoxin, a selective BK channel inhibitor, in DSM strips isolated from NDO patients. These results reveal the novel finding that NDO is associated with decreased DSM BK channel expression and function leading to increased DSM excitability and contractility. BK channel openers or BK channel gene transfer could be an alternative strategy to control NDO. Future clinical trials are needed to evaluate the value of BK channel opening drugs or gene therapies for NDO treatment and to identify any possible adverse effects.
Highlights
Overactive bladder (OAB) is described as urgency, with or without incontinence, usually associated with frequency and nocturia [1]
The Relative Expression Levels of BKa Subunit mRNA is Significantly Decreased in neurogenic detrusor overactivity (NDO) detrusor smooth muscle (DSM)
The changes in BKb1 and BKb4 subunits in NDO DSM compared to controls were not statistically significant and were evaluated at 1.1-fold and 1.6-fold decrease, respectively (P.0.05; Fig. 1)
Summary
Overactive bladder (OAB) is described as urgency, with or without incontinence, usually associated with frequency and nocturia [1]. Patients with various neurological diseases often develop voiding dysfunction which presents clinically as OAB [2] These OAB symptoms are often caused by dysfunction of the neurological control mechanisms subserving bladder function. When such a condition is the result of urodynamically demonstrable involuntary bladder contractions, it is termed neurogenic detrusor overactivity (NDO). Aside from the clinical symptoms of frequency, urgency and incontinence, high pressure involuntary contractions of DSM in patients with NDO may eventually lead to irreversible changes in DSM Such changes may result in decreased bladder compliance with associated high intravesical pressure during the bladder filling phase, and if left untreated may lead to deterioration of the upper urinary tract [3,4,5]
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