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The beta‐3 adrenoceptor agonist, mirabegron relaxes isolated prostate from human and rabbit: New therapeutic indication?
Author(s) -
Calmasini Fabiano B.,
Candido Tuany Z.,
Alexandre Eduardo C.,
D'Ancona Carlos A.,
Silva Daniel,
de Oliveira Marco Antonio,
De Nucci Gilberto,
Antunes Edson,
Mónica Fabíola Z.
Publication year - 2015
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22930
Subject(s) - mirabegron , prostate , phenylephrine , medicine , agonist , overactive bladder , endocrinology , iberiotoxin , pharmacology , urology , receptor , vasodilation , pathology , alternative medicine , cancer , blood pressure
BACKGROUND Alpha1 (α1)‐blockers, 5‐alpha reductase and phosphodiesterase type‐5 inhibitors are pharmacological classes currently available for benign prostatic hyperplasia (BPH) treatment. Mirabegron, a beta‐3 adrenoceptor (β3‐AR) agonist has been approved for the therapy of overactive bladder and may constitute a new therapeutic option for BPH treatment. This study is aimed to evaluate the in vitro effects of mirabegron in human and rabbit prostatic smooth muscle. METHODS In rabbit prostate , electrical field stimulation (EFS)‐induced contraction and concentration‐response curve (CRC) to mirabegron in phenylephrine pre‐contracted tissues were carried out. The potency (pEC 50 ) and maximal response (E max ) values were determined. In human prostate, CRC to phenylephrine was carried out in the absence and presence of mirabegron. Immunohistochemistry analysis for β3‐AR was also carried out. RESULTS In human prostate, immunohistochemistry analysis revealed the presence of β3‐AR on the transition zone and mirabegron reduced by 42% the phenylephrine‐induced contractions. In rabbit prostate, mirabegron produced concentration‐dependent relaxations (pEC 50 : 6.01 ± 0.12; E max : 106 ± 3%), which were fully resistant to the blockade of β1‐AR and β2‐AR. The β3‐AR blocker L748,337 caused a six‐fold rightward shift in mirabegron‐induced relaxations. Mirabegron (10 μM) reduced by 63% the EFS‐induced contractions. Inhibitors of nitric oxide (L‐NAME) and of soluble guanylate cyclase (ODQ) along with a cocktail of K+ channel blockers (apamin, charybdotoxin, glibenclamide, tetraethylammonium) all failed to significantly affect the mirabegron‐induced rabbit relaxations. CONCLUSION Mirabegron relaxes prostatic smooth muscle, providing an experimental support for the clinical investigation of its combination with an α1‐blockers or PDE5 inhibitors in the treatment of BPH. Prostate 75:440–447, 2015 . © 2014 Wiley Periodicals, Inc.