The Modulation Of Detrusor Contractility By Agents Influencing Ion Channel Activity

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.