Effects of potassium channel modulators on myogenic spontaneous phasic contractile activity in human detrusor from neurogenic patients

• Published in: BJU international 2011-08, Vol.108 (4), p.604-611
• Main Authors: Oger, Stephanie, Behr‐Roussel, Delphine, Gorny, Diane, Bernabé, Jacques, Comperat, Eva, Chartier‐Kastler, Emmanuel, Denys, Pierre, Giuliano, Francois
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Adult; Aged; Apamin - pharmacology; Benzimidazoles - pharmacology; Biological and medical sciences; bladder; Cancer; Carbon dioxide; Case-Control Studies; Contractility; glibenclamide; Glyburide - pharmacology; Humans; In Vitro Techniques; ion channels; Medical sciences; Membrane Transport Modulators - pharmacology; Middle Aged; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Nephrology. Urinary tract diseases; neurogenic detrusor overactivity; Neuromodulation; Peptides - pharmacology; pharmacology; pinacidil; Pinacidil - pharmacology; Potassium Channel Blockers - pharmacology; Potassium channels; Potassium channels (calcium-gated); Potassium Channels - drug effects; spontaneous contractions; Urinary bladder; Urinary Bladder, Overactive - drug therapy; Urinary Bladder, Overactive - etiology; Urinary Bladder, Overactive - physiopathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; urothelium; Urothelium - drug effects
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1111/j.1464-410X.2010.09935.x

OBJECTIVE To characterize the spontaneous contractile activity (SCA) developed by detrusor from patients with neurogenic detrusor overactivity (NDO) because the alteration of detrusor properties plays a critical role in the pathogenesis of detrusor overactivity, as well as to evaluate the role of KATP and KCa channels on this SCA because these channels regulate detrusor SCA in many species, including humans without overactive bladder (OAB). PATIENTS AND METHODS Human bladder samples were obtained from 44 patients undergoing cystectomy for bladder cancer with no known OAB symptoms and from 38 patients suffering from urodynamically diagnosed NDO. Detrusor strips with or without urothelium/suburothelium were mounted isometrically in organ baths filled with Krebs‐HEPES (37 °C; 95% O2/5% CO2). Strips were incubated with 10 µm pinacidil (KATP opener) followed by 10 µm glibenclamide (KATP blocker). In another set of experiments, strips were incubated with 30 µm NS‐1619 (BKCa opener) followed by 100 nm iberiotoxin (BKCa blocker) or with 100 nm apamin (SKCa blocker). RESULTS SCA occurred more frequently with larger amplitude and area under the curve in detrusor strips from NDO patients compared to control patients. The presence of urothelium/suburothelium did not significantly modify SCA in either patient population. Pinacidil markedly inhibited SCA of detrusor strips from control and NDO patients. This effect was reversed by glibenclamide. By contrast, NS‐1619 followed by iberiotoxin did not elicit any significant changes in SCA from NDO patients, contrary to control patients. CONCLUSIONS KATP and SKCa channels regulate SCA of NDO patients’ detrusor strips. By contrast, BKCa channels are not involved in the regulation of detrusor SCA in NDO patients, whereas they regulate SCA in control patients. These results should be considered in the development of K+ channels openers for the treatment of NDO. Moreover, SCA observed in vitro should be regarded as an in vitro modelling of human NDO.