MP17-05 POTENTIAL NOVEL TARGET FOR TREATMENT OF OVERACTIVE BLADDER: TRANSIENT RECEPTOR POTENTIAL MELASTATIN 4 CHANNEL IN HUMAN URINARY BLADDER

Abstract

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology1 Apr 2014MP17-05 POTENTIAL NOVEL TARGET FOR TREATMENT OF OVERACTIVE BLADDER: TRANSIENT RECEPTOR POTENTIAL MELASTATIN 4 CHANNEL IN HUMAN URINARY BLADDER Kiril Hristov, Shankar Parajuli, Amy Smith, John Malysz, Eric Rovner, and Georgi Petkov Kiril HristovKiril Hristov More articles by this author , Shankar ParajuliShankar Parajuli More articles by this author , Amy SmithAmy Smith More articles by this author , John MalyszJohn Malysz More articles by this author , Eric RovnerEric Rovner More articles by this author , and Georgi PetkovGeorgi Petkov More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.526AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Transient receptor potential melastatin 4 (TRPM 4) channels have been recently identified as potential regulators of detrusor smooth muscle (DSM) excitability and contractility in rodents; however, their expression and function in human DSM remains largely unexplored. Here, we provide a novel insight into a functional role of TRPM4 channels in human DSM. METHODS We used a multidisciplinary experimental approach including: RT-PCR, Western blot, immunohistochemistry and immunocytochemistry, amphotericin-perforated patch-clamp electrophysiology on native freshly-isolated human DSM cells, as well as functional studies on DSM contractility of DSM isolated strips from donor patients, and the novel TRPM4 channel inhibitor 9-phenathrol. RESULTS RT-PCR experiments detected mRNA message for TRPM4 channels in whole DSM tissue and single DSM cells. Western blot analysis and immunohistochemical staining revealed TRPM4 protein expression in whole DSM tissue. Immunocytochemical experiments further detected TRPM4 protein expression in isolated single DSM cells. Voltage-clamp experiments on freshly-isolated native human DSM cells showed that inhibition of TRPM4 channels with 9-phenathrol significantly decreased the transient inward cation currents (TICCs) activity, when recorded at -70 mV. Pretreatment of DSM cells with xestospongin C, an inositol-3-phosphate receptor inhibitor, abolished the TICCs. Current-clamp experiments demonstrated that inhibition of TRPM4 channels with 9-phenathrol hyperpolarized DSM cell resting membrane potential by ∼11 mV. In vitro functional studies on DSM contractility revealed that TRPM4 channel inhibitor 9-phenantrol significantly attenuated the spontaneous phasic, carbachol-induced, and nerve-evoked contractions in human DSM isolated strips in a concentration-dependent manner. CONCLUSIONS Our results demonstrate the novel finding that TRPM4 channels are expressed in human DSM and support the concept that they regulate human DSM excitability and contractility. Therefore, TRPM4 channels may be considered as novel targets for treatment of overactive bladder. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e136-e137 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Kiril Hristov More articles by this author Shankar Parajuli More articles by this author Amy Smith More articles by this author John Malysz More articles by this author Eric Rovner More articles by this author Georgi Petkov More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...