PD03-10: Concentration-dependent antagonism of α1-adrenergic smooth muscle contractions in human prostate tissues, and bidirectional effects on stromal cell growth by the dual β- and α1-adrenergic antagonist carvedilol
Friday, May 3, 2024 8:30 AM to 8:40 AM · 10 min. (US/Central)
303A
Abstract
Information
Full Abstract and Figures
Author Block
Hu Sheng*, Alexander Tamalunas, Raphaela Waidelich, Christian G. Stief, Munich, Germany, Martin Hennenberg, Munichc, Germany
Introduction
Carvedilol shows a unique pharmacological profile among ß-blockers, including antagonism of a1-adrenoceptors and activation of G protein-independent signaling, apart from antagonizing ß-adrenoceptors. Even though it is a commonly used antihypertensive and a1-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 a1-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 a1-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 a1-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 a1-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).
Author Block
Hu Sheng*, Alexander Tamalunas, Raphaela Waidelich, Christian G. Stief, Munich, Germany, Martin Hennenberg, Munichc, Germany
Introduction
Carvedilol shows a unique pharmacological profile among ß-blockers, including antagonism of a1-adrenoceptors and activation of G protein-independent signaling, apart from antagonizing ß-adrenoceptors. Even though it is a commonly used antihypertensive and a1-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 a1-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 a1-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 a1-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 a1-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).