Pd03-02 Small Molecule Gap Inhibitor Qs11 Promotes Adrenergic and Non-Adrenergic Prostate Smooth Muscle Contraction

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD03)1 May 2024PD03-02 SMALL MOLECULE GAP INHIBITOR QS11 PROMOTES ADRENERGIC AND NON-ADRENERGIC PROSTATE SMOOTH MUSCLE CONTRACTION Alexander J. Tamalunas, Amin Wendt, Florian Springer, Nikolaus Eitelberger, Victor Vigodski, Moritz Trieb, Felix Schierholz, Beata Rutz, Anna Ciotkowska, Giuseppe Magistro, Christian G. Stief, and Martin Hennenberg Alexander J. TamalunasAlexander J. Tamalunas , Amin WendtAmin Wendt , Florian SpringerFlorian Springer , Nikolaus EitelbergerNikolaus Eitelberger , Victor VigodskiVictor Vigodski , Moritz TriebMoritz Trieb , Felix SchierholzFelix Schierholz , Beata RutzBeata Rutz , Anna CiotkowskaAnna Ciotkowska , Giuseppe MagistroGiuseppe Magistro , Christian G. StiefChristian G. Stief , and Martin HennenbergMartin Hennenberg View All Author Informationhttps://doi.org/10.1097/01.JU.0001009388.01015.e5.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate smooth muscle contraction is one of the main targets for medical treatment in LUTS/BPH. Due to an unfavorable balance between side effects and limited efficacy, current medications cause high discontinuation rates. Agonist-induced smooth muscle contractions are mediated by activation of a1-adrenoceptors, endothelin and thromboxane, and their intracellular signaling pathways including monomeric GTPases. In general, GTPases are deactivated by GTPase-activating proteins (GAP), activating the GTPase activity and thus deactivating signaling by the GTPase. Recently, we could show, that the small monomeric GTPase ARF6 is involved in prostate smooth muscle contraction. Here, we examined the effect of QS11, a small molecule ARF GAP inhibitor, on agonist-induced human prostate smooth muscle contraction. METHODS: Prostate tissues were obtained from patients undergoing radical prostatectomy for prostate cancer (n=32 patients). Contractility of prostate strips was then assessed in an organ bath. Data are presented as mean±standard deviation, while group p-value is given in the diagrams and # indicates p<0.05 for each concentration. RESULTS: Noradrenaline-induced adrenergic contractions were increased up to 43±23.1% with QS11 (6µM) for concentrations of 1-100 µM (p=0.012 for QS11 vs. control; Figure 1A), up to 49±21.9% for 1-100µM of phenylephrine-induced contractions (p<0.001 for QS11 vs. control; Figure 1B), and up to 58±17.6% for 1-100µM of methoxamine-induced contractions (p<0.001 for QS11 vs. control; Figure 1C). Additionally, QS11 promoted non-adrenergic contraction by thromboxane A2 analogue U46619 up to 55±37.4% for 1-300µM of U46619-induced contractions (p<0.001 for QS11 vs. control; Figure 1E) and EFS-induced neurogenic contractions up to 51±33.9% for 2-32 Hz (p=0.002 for QS11 vs. control; Figure 1F). However, there was no effect on endothelin-1 induced contractions (Figure 1D). CONCLUSIONS: QS11-sensitive GAPs are involved in regulation of human prostate smooth muscle contraction, by control of ARF6 GTPase activity. Knowledge about GEFs and GAPs involved in smooth muscle contraction is still limited. However, increased understanding of prostate smooth muscle contraction may assist in developing new pharmaceutical targets for LUTS medication in the future. Download PPT Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e76 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Alexander J. Tamalunas More articles by this author Amin Wendt More articles by this author Florian Springer More articles by this author Nikolaus Eitelberger More articles by this author Victor Vigodski More articles by this author Moritz Trieb More articles by this author Felix Schierholz More articles by this author Beata Rutz More articles by this author Anna Ciotkowska More articles by this author Giuseppe Magistro More articles by this author Christian G. Stief More articles by this author Martin Hennenberg More articles by this author Expand All Advertisement PDF downloadLoading ...