Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3 -adrenoceptor activation and α1 -adrenoceptor blockade.
BACKGROUND
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.


OBJECTIVE
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).


METHODS
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.


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).


CONCLUSIONS
The effects of mirabegron in urethral smooth muscle are the result of β3 -adrenoceptor agonism together with α1A and α1D -adrenoceptor antagonism.
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil.
E C
EC
Alexandre
Department of Pharmacology, Institute of Biosciences, University of São Paulo State (UNESP), Botucatu, São Paulo, Brazil.
L R
LR
Kiguti
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil.
F B
FB
Calmasini
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil.
F H
FH
Silva
Department of Pharmacology, Institute of Biosciences, University of São Paulo State (UNESP), Botucatu, São Paulo, Brazil.
K P
KP
da Silva
Hematology and Hemotherapy Center, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.
R
R
Ferreira
Department of Pharmacology, Institute of Biosciences, University of São Paulo State (UNESP), Botucatu, São Paulo, Brazil.
C A
CA
Ribeiro
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil.
F Z
FZ
Mónica
Department of Pharmacology, Institute of Biosciences, University of São Paulo State (UNESP), Botucatu, São Paulo, Brazil.
A S
AS
Pupo
Department of Pharmacology, University of Campinas (UNICAMP), Campinas, Brazil.
E
E
Antunes
D000083:Acetanilides / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014521:Urethra / Q000187:drug effects* / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D000083:Acetanilides; D058668:Adrenergic alpha-1 Receptor Antagonists; D058667:Adrenergic beta-3 Receptor Agonists; D000627:Aminophenols; C120576:L 748,337; D011942:Receptors, Adrenergic, alpha; D013449:Sulfonamides; D013844:Thiazoles; C520025:mirabegron