Mirabegron is the first β 3 -adrenoceptor agonist approved for treatment of overactive bladder syndrome. This study aimed to investigate the effects of β 3 -adrenoceptor agonist mirabegron in mouse urethra. The possibility that mirabegron also exerts α 1 -adrenoceptor antagonism was also tested in rat smooth muscle preparations presenting α 1A -(vas deferens and prostate), α 1D -(aorta) and α 1B -adrenoceptors (spleen). EXPERIMENTAL APPROACHFunctional 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 α 1 -adrenoceptors, as well as β-adrenoceptor mRNA expression and cyclic AMP measurements in mouse urethra, were performed. KEY RESULTSMirabegron produced concentration-dependent urethral relaxations that were shifted to the right by the selective β 3 -adrenoceptor antagonist L-748,337 but unaffected by β 1 -and β 2 -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 α 1 -adrenoceptor agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of α 1 -adrenoceptors in urethra, vas deferens and prostate (α 1A -adrenoceptor, pA 2 ≅ 5.6) and aorta (α 1D -adrenoceptor, pA 2 ≅ 5.4) but not in spleen (α 1B -adrenoceptor). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant α 1A -and α 1D -adrenoceptors (pK i ≅ 6.0). CONCLUSION AND IMPLICATIONSThe effects of mirabegron in urethral smooth muscle are the result of β 3 -adrenoceptor agonism together with α 1A and α 1D -adrenoceptor antagonism. Abbreviations

Morphological and physiological changes in the vasculature have been described in the evolution and maintenance of hypertension. Hypertension-induced vascular dysfunction may present itself as a contributing, or consequential factor, to vascular remodeling caused by chronically elevated systemic arterial blood pressure. Changes in all vessel layers, from the endothelium to the perivascular adipose tissue (PVAT), have been described. This mini-review focuses on the current knowledge of the structure and function of the vessel layers, specifically muscular arteries: intima, media, adventitia, PVAT, and the cell types harbored within each vessel layer. The contributions of each cell type to vessel homeostasis and pathophysiological development of hypertension will be highlighted.

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.

BackgroundSickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease.ObjectiveThus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide—cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice.MethodsConcentration–response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured.ResultsThe neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected.ConclusionOur study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice.

Mirabegron was able to completely restore the urinary alterations seen in the bladder from obese mice.