PD03-10 CONCENTRATION-DEPENDENT ANTAGONISM OF α ₁ -ADRENERGIC SMOOTH MUSCLE CONTRACTIONS IN HUMAN PROSTATE TISSUES, AND BIDIRECTIONAL EFFECTS ON STROMAL CELL GROWTH BY THE DUAL ß- AND α ₁ -ADRENERGIC ANTAGONIST CARVEDILOL

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD03)1 May 2024PD03-10 CONCENTRATION-DEPENDENT ANTAGONISM OF α1-ADRENERGIC SMOOTH MUSCLE CONTRACTIONS IN HUMAN PROSTATE TISSUES, AND BIDIRECTIONAL EFFECTS ON STROMAL CELL GROWTH BY THE DUAL ß- AND α1-ADRENERGIC ANTAGONIST CARVEDILOL Hu Sheng, Alexander Tamalunas, Raphaela Waidelich, Christian G. Stief, and Martin Hennenberg Hu ShengHu Sheng , Alexander TamalunasAlexander Tamalunas , Raphaela WaidelichRaphaela Waidelich , Christian G. StiefChristian G. Stief , and Martin HennenbergMartin Hennenberg View All Author Informationhttps://doi.org/10.1097/01.JU.0001009388.01015.e5.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Carvedilol shows a unique pharmacological profile among ß-blockers, including antagonism of α1-adrenoceptors and activation of G protein-independent signaling, apart from antagonizing ß-adrenoceptors. Even though it is a commonly used antihypertensive and α1-adrenoceptors are essential for treatment of voiding symptoms in BPH, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on prostate stromal cell growth. METHODS: Contractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α1-agonists. Growth of cultured stromal cells was assessed by colony formation. RESULTS: Concentration response curves for phenylephrine, methoxamine and noradrenaline were concentration-dependently rightshifted by carvedilol (0.01-10 µM), with rightshifts around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes or more with 10 µM carvedilol. Rightshifts were reflected by increases in EC50 values for α1-agonists, while Emax values were unchanged. EC50 values for phenylephrine were increased by 0.48 [-0.04 to 1.01] magnitudes (MD logM) with 100 nM carvedilol, 0.92 [0.14 to 1.69] with 1 µM, and 1.99 [1.37 to 2.67] with 10 µM, EC50 values for methoxamine by 0.67 [0.34 to 1.00] magnitudes with 100 nM, 1.17 [0.74 to 1.61] with 1 µM, and 2.21 [1.46 to 2.96] with 10 µM carvedilol, and EC50 values for 0.28 [0 to 0.54] with 10 nM, 0.39 [0.07 to 0.73] with 100 nM, 0.54 [0.3 to 0.79] with 1 µM, and 1.83 [1.01 to 2.64] with 10 µM carvedilol. EFS-induced contractions were reduced by 21-54% with 10 nM to 1 µM, and by 94% by 10 µM carvedilol. Colony numbers of stromal cells were increased by 500 nM carvedilol (1.5 fold [1.4-1.7] of controls), but reduced by 78% [68-88] by 1 µM, and 98% [95-101] by 10 µM. Colony-covered areas were reduced by all concentrations (by 40% [36-45] by 500 nM, 81% [77-85] by 1 µM, 90% [92-92] by 10 µM. CONCLUSIONS: Carvedilol antagonizes α1-adrenoceptors in the human prostate, starting with concentrations in ranges of plasma levels (115-315 nM). Maximum effects, including inhibition of EFS-induced contractions resemble those of α1-blockers used for treatment of voiding symptoms, but require concentrations beyond plasma levels. Opposing effects on stromal cell growth are potentially attributed to "biased agonism", by G protein-independent signaling. Source of Funding: Deutsche Forschungsgemeinschaft (DFG, HE 5825/9-1); China Scholarship Council (CSC, 202108430037) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e79 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Hu Sheng More articles by this author Alexander Tamalunas More articles by this author Raphaela Waidelich 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 ...