Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

Abstract

Introduction: Mirabegron is available for treatment of storage symptoms in overactive bladder, which may be improved by β3-adrenoceptor-induced bladder smooth muscle relaxation. In addition to storage symptoms, lower urinary tract symptoms in men include obstructive symptoms attributed to benign prostatic hyperplasia, caused by increased prostate smooth muscle tone and prostate enlargement. In contrast to the bladder and storage symptoms, effects of mirabegron on prostate smooth muscle contraction and obstructive symptoms are poorly understood. Evidence from non-human smooth muscle suggested antagonism of α1-adrenoceptors as an important off-target effect of mirabegron. As α1-adrenergic contraction is crucial in pathophysiology and medical treatment of obstructive symptoms, we here examined effects of mirabegron on contractions of human prostate tissues and on proliferation of prostate stromal cells.Methods: Contractions were induced in an organ bath. Effects of mirabegron on proliferation, viability, and cAMP levels in cultured stromal cells were examined by EdU assays, CCK-8 assays and enzyme-linked immunosorbent assay.Results: Mirabegron in concentrations of 5 and 10 μM, but not 1 µM inhibited electric field stimulation-induced contractions of human prostate tissues. Mirabegron in concentrations of 5 and 10 µM shifted concentration response curves for noradrenaline-, methoxamine- and phenylephrine-induced contractions to the right, including recovery of contractions at high concentrations of α1-adrenergic agonists, increased EC50 values, but unchanged Emax values. Rightshifts of noradrenaline concentration response curves and inhibition of EFS-induced contractions were resistant to L-748,337, l-NAME, and BPIPP. 1 µM mirabegron was without effect on α1-adrenergic contractions. Endothelin-1- and U46619-induced contractions were not affected or only inhibited to neglectable extent. Effects of mirabegron (0.5–10 µM) on proliferation and viability of stromal cells were neglectable or small, reaching maximum decreases of 8% in proliferation assays and 17% in viability assays. Mirabegron did not induce detectable increases of cAMP levels in cultured stromal cells.Conclusion: Mirabegron inhibits neurogenic and α1-adrenergic human prostate smooth muscle contractions. This inhibition may be based on antagonism of α1-adrenoceptors by mirabegron, and does not include activation of β3-adrenoceptors and requires concentrations ranging 50-100fold higher than plasma concentrations reported from normal dosing. Non-adrenergic contractions and proliferation of prostate stromal cells are not inhibited by mirabegron.

Mirabegron attenuates porcine ureteral contractility via α1-adrenoceptor antagonism

“…Additionally, during its regulatory submission, it was also indicated that this drug potentially antagonises α 1 -adrenoceptors (U.S. Food and Drug Administration 2012 ). In our ureteral study, mirabegron, at 10 μM, also decreased maximum contractions which was not observed in the urethra (Alexandre et al 2016 ) or prostate (Huang et al 2021 ). Due to this decrease in maximum contractions, we could only calculate apparent pA 2 values using shifts at the lower part of the concentration curves.…”

“…Our agonist concentration response studies showed that the presence of mirabegron, at 1 μM and higher, was capable of antagonising phenylephrine-induced contractility. This is not surprising, as previous studies have reported that similar concentrations of mirabegron antagonises other receptors including α 1 -adrenoceptor stimulation in the urethra (Alexandre et al 2016 ) and prostate (Alexandre et al 2016 ; Huang et al 2021 ), and muscarinic receptors in the pig and human detrusor (Maki et al 2019 ; Yamada et al 2021 ). Additionally, during its regulatory submission, it was also indicated that this drug potentially antagonises α 1 -adrenoceptors (U.S. Food and Drug Administration 2012 ).…”

“…Mirabegron is proposed to function by activating the β 3 -adrenoceptors in the human detrusor smooth muscle, inducing a relaxation during the storage phase of micturition (Svalo et al 2013 ; Takasu et al 2007 ). Previous studies have also shown that mirabegron is capable of relaxing other smooth muscle tissues of the urinary tract like the urethra and the prostate (Alexandre et al 2016 ; Huang et al 2021 ). Given the proximity of the ureter, particularly the distal section, to these organs, there has been recent interest in purposing mirabegron as a medical expulsive therapy alternative to tamsulosin to promote stone passage (Tang et al 2021 ).…”

Is the β3-Adrenoceptor a Valid Target for the Treatment of Obesity and/or Type 2 Diabetes?

“…It has been speculated that such adverse effects are related to a phenyl ethanolamine backbone, which is present in mirabegron and several other β 3 -AR agonists and may cause indirect sympathomimetic activity [197]. Moreover, at least mirabegron has additional off-target effects such as antagonism at α 1adrenoceptors [198][199][200]. Such off-target effects were neither reported nor are expected for the β 3 -AR agonists with other chemical backbones.…”

β3 adrenoceptor agonist mirabegron protects against right ventricular remodeling and drives Drp1 inhibition

“…H9c2 cells with 60-70% confluency were serum starved and were then treated with angiotensin II (Ang II) (600 nM), mirabegron (10 µM), Compound C (10 µM), and/or mdvid1 (20 µM) simultaneously as stated in the figures for 24 hours. The doses of the treatments were based on published studies (17)(18)(19)(20). The cells were harvested for immunoblotting.…”