The Modulation Of Detrusor Contractility By Agents Influencing Ion Channel Activity

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Abstract

Background: This study specified the role of several significant ion channels regulating the metabolism of calcium ions in contraction and relaxation of human detrusor muscle in order to identify possible target for future drugs that are capable of treating diseases resulting from impaired detrusor activity, e.g. overactive bladder. Although this disease can be successfully treated with muscarinic receptor antagonists or β3 agonist, many patients may not be suitable for chronic therapy, especially due to the relatively high side effects of the treatment.

Material and Methods: The study used the isolated detrusor tissue samples, which were obtained from the macroscopic healthy tissue of urinary bladder from 19 patients undergoing a total prostatectomy because of localized prostate cancer. Each biological sample was prepared into 8 strips. We used oxybutynin and mirabegron as control drugs and several blockers of specific subtypes calcium and potassium ion channels as tested substances. The contractility of bladder was investigated by an organ tissue bath method in vitro and contraction was induced by carbachol.

Results: The amplitude of contraction was successfully decreased by positive control drugs and, from tested agents, the comparable effect had the substance capable of influencing IP3 receptors and Orai-STIM channels and combination consisting of drugs possessing an inhibitory effect on IP3 receptors, L- and T-type voltage-gated calcium channels and Orai-STIM channels.

Conclusion: The present work represents a new finding about handling Ca2+ in urinary bladder contraction and pointed to a dominant role of IP3 receptor-mediated pathway in the regulation of Ca2+ metabolism, which may represent a future strategy in pharmacotherapy of impaired detrusor activity.

[1] Abrams P, Kelleher C, Staskin D et al. Combination Treatment with Mirabegron and Solifenacin in Patients with Overactive Bladder: Efficacy and Safety Results from a Randomised, Double-blind, Doseranging, Phase 2 Study (Symphony). Eur Urol. 2015;67:577-588.

[2] Andersson KE. Drug therapy of overactive bladder – What is comming next? Korean J. Urol. 2015;56:673-679.

[3] Cernecka H, Kersten K, Maarsingh H et al. β3-Adrenoceptormediated relaxation of rat and human urinary bladder: roles of BKCa channels and Rho kinase. Naunyn Schmiedebergs Arch. Pharmacol. 2015;388:749–759.

[4] DeHaven WI, Smyth JT, Boyles RR, et al. Complex Actions of 2-Aminoethyldiphenyl Borate on Store-operated Calcium Entry. J Biol Chem. 2008; 283:19265

[5] Feske S, Gwack Y, Prakriya M et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature. 2016;441:179–185.

[6] Fox J, Weisberg S. An R Companion to Applied Regression, Second Edition. Thousand Oaks CA: Sage. 2011

[7] Franova S, Janicek F, Visnovsky J et al. Utero-relaxant effect of PDE4-selective inhibitor alone and in simultaneous administration with β2-mimetic on oxytocin-induced contractions in pregnant myometrium. Int J Gynaecol Obstet. 2009;35:20-25.

[8] Gormley EA, Lightner DJ, Faraday M, Vasavada SP. Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline Amendment. J Urol. 2015;193:1-9.

[9] Hedge SS. Muscarinic receptors in the bladder: from basic research to therapeutics. Br. J. Pharmacol. 2006; 147:S80-S87.

[10] Hill-Eubanks DC, Werner ME, Heppner TJ, Nelson MT. Calcium Signaling in Smooth Muscle. Cold Spring Harb. Perspect. Biol. 2011;3:a004549.

[11] Maman K, Aballea S, Nazir J et al. Comparative Efficacy and Safety of Medical Treatments for the Management of Overactive Bladder: A Systematic Literature Review and Mixed Treatment Comparison. Eur Urol. 2014;65:755-765.

[12] Mair P, Schoenbrodt F, Wilcox R. WRS2: Wilcox robust estimation and testing. 2016

[13] Parajuli SP, Zheng YM, Levin R, Wang YX. Big-conductance Ca2+- activated K+ channels in physiological and pathophysiological urinary bladder smooth muscle cells. Channels. 2016;10:355-364.

[14] R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, https://www.R-project.org/. 2015

[15] Rajalabaya R, Leen G, Chellian J, Chakravarthi S, David SR. Tolterodine Tartrate Proniosomal Gel Transdermal Delivery for Overactive Bladder. Pharmaceutics. 2016;8:27.

[16] Sharaf A, Hashim H. Profile of mirabegron in the treatment of overactive bladder: place in therapy. Drug Des Devel Ther. 2017;11:463–467.

[17] Sui GP, Wu C, Severs N, Newgreen D, Fry CH. The association between T-type Ca2+ current and outward current in isolated human detrusor cells from stable and overactive bladders. BJU International. 2007;99:436–441.

[18] Sutovska M., Nosalova G., Franova S. The role of potassium ion channels in cough and other reflexes of the airways. J Physiol Pharmacol. 2007;58:673-683.

[19] Tanahashi Y, Wang B, Murakami Y et al.. Inhibitory effects of SKF96365 on the activities of K+ channels in mouse small intestinal smooth muscle cells. J. Vet. Med. Sci. 2016;78(2):203-211.

[20] Zhao B, Zhong X, Bai X, Wang Q, Song B, Li L. Changes in storeoperated calcium channels in rat bladders with detrusor overactivity. Urology. 2014;84:491.e1-6.

European Pharmaceutical Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianae (formerly)

Journal Information


CiteScore 2017: 0.24

SCImago Journal Rank (SJR) 2017: 0.129
Source Normalized Impact per Paper (SNIP) 2017: 0.140

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