MP45-11 NEW STRATEGIES FOR INHIBITION OF NON-ADRENERGIC PROSTATE SMOOTH MUSCLE CONTRACTION BY PHARMACOLOGIC INTERVENTION

Abstract

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology1 Apr 2018MP45-11 NEW STRATEGIES FOR INHIBITION OF NON-ADRENERGIC PROSTATE SMOOTH MUSCLE CONTRACTION BY PHARMACOLOGIC INTERVENTION Qingfeng Yu, Christian Gratzke, Paul Kuppermann, Annika Herlemann, Yiming Wang, Frank Strittmatter, Raphaela Waidelich, Christian Stief, and Martin Hennenberg Qingfeng YuQingfeng Yu More articles by this author , Christian GratzkeChristian Gratzke More articles by this author , Paul KuppermannPaul Kuppermann More articles by this author , Annika HerlemannAnnika Herlemann More articles by this author , Yiming WangYiming Wang More articles by this author , Frank StrittmatterFrank Strittmatter 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/10.1016/j.juro.2018.02.1450AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Inhibition of prostate smooth muscle contraction by a1-adrenoceptor antagonists (a1-blockers) is the first option for medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). In fact, increased prostate smooth muscle tone may drive urethral obstruction and LUTS. However, the efficacy of α1-blockers is limited to 50%, because non-adrenergic mediators including endothelin-1 and thromboxane A2 (TXA2) increase prostate smooth muscle tension in parallel to α1-adrenoceptors and may therefore keep urethral obstruction despite therapy with α1-blockers. Consequently, future options with highest efficacy need to target α1-adrenergic and non-adrenergic contractions at once. Recently, several compounds have been reported to inhibit adrenergic prostate contraction, but their effects on non-adrenergic contraction are still unknown. Here, we examined effects of Rac-GTPase inhibitors and of a Src family kinase (SFK) inhibitor on non-adrenergic prostate contractions. METHODS Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath, where they were induced by the α1-adrenoceptor agonist methoxamine, the TXA2 analog U46619, or by endothelin-1. RESULTS Methoxamine, U46619, and endothelin-1 induced concentration-dependent contractions of prostate strips. Inhibitory effects of the Rac inhibitors EHT1864 (100 µM) and NSC23766 (100 µM) and of the SFK inhibitor AZM475721 (10 µM) on α1-adrenergic contraction were confirmed by inhibition of methoxamine-induced contractions by all three inhibitors. EHT1864 caused significant inhibition of endothelin-1- and U46619-induced contractions, which was observed at 0.1-3 μM of endothelin-1 (p<0.001 between EHT1864 and control group), and at 1-30 μM of U46619 (p<0.001 between EHT1864 and control group). NSC23766 caused significant inhibition of U46619-induced contractions, which was observed at 3-10 µM of U46619 (p<0.001 between NSC23766 and control group). NSC23766 did not change endothelin-1-induced contractions. AZM475721 did not change U46619- or endothelin-1-induced contractions. CONCLUSIONS From the three examined inhibitors, EHT1864 is the most promising from a translational view, as it inhibited TXA2- and endothelin-1-induced besides α1-adrenergic prostate contractions. This reflects divergent pharmacologic profiles of EHT1864 and NSC23766, although both are Rac-GTPase inhibitors. In vivo, urodynamic effects of EHT1864, but not of AZM475721 may exceed those of α1-blockers. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e601-e602 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Qingfeng Yu More articles by this author Christian Gratzke More articles by this author Paul Kuppermann More articles by this author Annika Herlemann More articles by this author Yiming Wang More articles by this author Frank Strittmatter 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 Advertisement PDF downloadLoading ...