MP06-10 INHIBITION OF HUMAN PROSTATE SMOOTH MUSCLE CONTRACTION BY THE INTEGRIN α2β1-SELECTIVE INHIBITOR BTT3033 AND THE INTEGRIN-LINKED KINASE INHIBITOR CPD22

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You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (MP06)1 Apr 2020MP06-10 INHIBITION OF HUMAN PROSTATE SMOOTH MUSCLE CONTRACTION BY THE INTEGRIN α2β1-SELECTIVE INHIBITOR BTT3033 AND THE INTEGRIN-LINKED KINASE INHIBITOR CPD22 Bingsheng Li*, Xiaolong Wang, Beata Rutz, Anna Ciotkowska, Christian Gratzke, Alexander Tamalunas, Raphaela Waidelich, Christian Stief, and Martin Hennenberg Bingsheng Li*Bingsheng Li* More articles by this author , Xiaolong WangXiaolong Wang More articles by this author , Beata RutzBeata Rutz More articles by this author , Anna CiotkowskaAnna Ciotkowska More articles by this author , Christian GratzkeChristian Gratzke More articles by this author , Alexander TamalunasAlexander Tamalunas More articles by this author , Raphaela WaidelichRaphaela Waidelich More articles by this author , Christian StiefChristian Stief More articles by this author , and Martin HennenbergMartin Hennenberg More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000820.010AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Integrins connect the cytoskeleton of cells to membranes and extracellular matrix, what is essential for force generation by smooth muscle contraction. Suprisingly, their role for contraction has not been tested yet in any organ. In the prostate, smooth muscle contraction is critical for lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins are composed by different subunits in different organs, so that subunit-specific inhibitors may be attractive to attain prostate-specific inhibition of smooth muscle contraction. Here we examined effects of the integrin α2β1 inhibitor BTT3033 and the integrin-linked kinase (ILK) inhibitor Cpd22 on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy (n=56 patients). Contraction of prostate strips was studied in an organ bath. Integrins and ILK were detected by Western blot and fluorescence staining. RESULTS: Electric field stimulation (EFS) induced frequency-dependent contractions of prostate tissues, which were inhibited by BTT3033 (1 µM) (55% inhibition at 32 Hz; p<0.004 for whole frequency-response curves; n=5) and Cpd22 (3 µM) (47% inhibition at 32 Hz, p<0.02, n=5). The α1-adrenoceptor agonists noradrenaline and methoxamine induced concentration-dependent, which were inhibited BTT3033 (1 µM) (p<0.004 for noradrenaline, n=5; p<0.03 for methoxamine, n=6), and by Cpd22 (3 µM) (p<0.008 for noradrenaline, n=6; p<0.02 for methoxamine, n=5). The thromboxane A2 analog U46619 induced concentration-dependent contractions, which were inhibited by BTT3033 (1 µM) (p<0.03, n=5), and by Cpd22 (p<0.001, n=5). Western blot analyses of prostate tissues revealed bands with sizes matching the expected sizes for integrin α2b, integrin β1 and ILK, which were observed in each included sample (n=9). Double fluorescence staining of prostate sections (n=5) resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. CONCLUSIONS: Integrin and ILK inhibitors inhibit agonist-induced and neurogenic prostate smooth muscle contraction in BPH. As integrins show organ-specific composition, targeting the prostate-specific integrin code by subunit-specific inhibitors may offer a promising approach to attain inhibition in the prostate, without side effects in the cardiovascular system. Source of Funding: Deutsche Forschungsgemeinschaft (DFG), Chinese Scholarship Council (CSC) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e54-e55 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bingsheng Li* More articles by this author Xiaolong Wang More articles by this author Beata Rutz More articles by this author Anna Ciotkowska More articles by this author Christian Gratzke More articles by this author Alexander Tamalunas More articles by this author Raphaela Waidelich More articles by this author Christian Stief More articles by this author Martin Hennenberg More articles by this author Expand All Advertisement PDF downloadLoading ...