title: Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca(2+)-activated K(+) channels.
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 Ca(2+)-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.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: Kiril L
authors.initials: KL
authors.lastname: Hristov
authors.forename: Serge A Y
authors.initials: SA
authors.lastname: Afeli
authors.forename: Shankar P
authors.initials: SP
authors.lastname: Parajuli
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Cheng
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rovner
authors.forename: Georgi V
authors.initials: GV
authors.lastname: Petkov
mesh_terms: D000368:Aged; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D053201:Urinary Bladder, Overactive / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; C064719:iberiotoxin