LINKED ARTICLE: This article is commented on by Michel, M. C., pp. 429-430 of 
this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.13379.
BACKGROUND AND PURPOSE: Mirabegron is the first β3 -adrenoceptor agonist 
approved for treatment of overactive bladder syndrome. This study aimed to 
investigate the effects of β3 -adrenoceptor agonist mirabegron in mouse urethra. 
The possibility that mirabegron also exerts α1 -adrenoceptor antagonism was also 
tested in rat smooth muscle preparations presenting α1A - (vas deferens and 
prostate), α1D - (aorta) and α1B -adrenoceptors (spleen).
EXPERIMENTAL APPROACH: Functional assays were carried out in mouse and rat 
isolated tissues. Competition assays for the specific binding of [(3) H]prazosin 
to membrane preparations of HEK-293 cells expressing each of the human α1 
-adrenoceptors, as well as β-adrenoceptor mRNA expression and cyclic AMP 
measurements in mouse urethra, were performed.
KEY RESULTS: Mirabegron produced concentration-dependent urethral relaxations 
that were shifted to the right by the selective β3 -adrenoceptor antagonist 
L-748,337 but unaffected by β1 - and β2 -adrenoceptor antagonists (atenolol and 
ICI-118,551 respectively). Mirabegron-induced relaxations were enhanced by the 
PDE4 inhibitor rolipram, and the agonist stimulated cAMP synthesis. Mirabegron 
also produced rightward shifts in urethral contractions induced by the α1 
-adrenoceptor agonist phenylephrine. Schild regression analysis revealed that 
mirabegron behaves as a competitive antagonist of α1 -adrenoceptors in urethra, 
vas deferens and prostate (α1A -adrenoceptor, pA2  ≅ 5.6) and aorta (α1D 
-adrenoceptor, pA2  ≅ 5.4) but not in spleen (α1B -adrenoceptor). The affinities 
estimated for mirabegron in functional assays were consistent with those 
estimated in radioligand binding with human recombinant α1A - and α1D 
-adrenoceptors (pKi  ≅ 6.0).
CONCLUSION AND IMPLICATIONS: The effects of mirabegron in urethral smooth muscle 
are the result of β3 -adrenoceptor agonism together with α1A and α1D 
-adrenoceptor antagonism.