In vitro and in vivo pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in rats

Abstract

To investigate the pharmacological properties of mirabegron in in vitro and in vivo, the effects on cAMP accumulation in Chinese hamster ovary (CHO) cells expressing rat β-adrenoceptors, the relaxant activity in isolated rat bladder smooth muscle, and the voiding effects in cerebral infarcted rats were evaluated. Mirabegron increased cAMP accumulation with EC(50) value and intrinsic activity of 19 nmol/L and 1.0, respectively, in CHO cells expressing rat β(3)-adrenoceptors. The EC(50) values and the intrinsic activities of mirabegron were 610 nmol/L and 0.6 for rat β(1)-adrenoceptors and were sumless and 0.1 for β(2)-adrenoceptors, respectively. Mirabegron showed concentration-dependent relaxant and full agonistic effects in rat bladder strips under passive tension with EC(50) value of 290 nmol/L. The concentration-response curve of mirabegron was affected neither by the β(1)-adrenoceptor selective antagonist CGP-20712A nor by the β(2)-adrenoceptor selective antagonist ICI-118,551. In in vivo studies with cerebral infarcted rats, a significant decrease in the volume voided per micturition compared with sham-operated rats was observed. Mirabegron dose-dependently increased the volume voided per micturition. In conclusion, we have extended the selectivity profile of mirabegron to rats and demonstrated that it is effective via stimulation of β(3)-adrenoceptors in a rat cerebral infarction model of detrusor overactivity.

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

“…In human embryonic kidney (HEK) cells stably transfected with human β 3 -adrenoceptors at a density of 121-fmol/mg protein, mirabegron and isoprenaline exhibited apparent affinities of 55 nM and 34 μM, respectively, in competition radioligand binding studies, and these affinities were not substantially altered in HEK cells transfected with several naturally occurring gene variants of the receptor ). In cyclic AMP accumulation experiments in these HEK cells, mirabegron and isoprenaline exhibited EC 50 values of 0.93 and 11.2 nM, respectively, and the efficacy of mirabegron relative to isoprenaline was 0.85, which is in good agreement with the findings in CHO cells (Hatanaka et al 2013b;Takasu et al 2007). The potency and efficacy of mirabegron also was not affected by genotype in these experiments.…”

“…Two studies on CHO cells transfected with human β-adrenoceptor subtypes were reported with rather similar results. Thus, mirabegron stimulated cyclic AMP accumulation via β 3 -adrenoceptors with EC 50 values of 22 nM (Takasu et al 2007) and 1.5 nM (Hatanaka et al 2013b), its efficacy relative to isoprenaline was 0.8 in both studies; in contrast, efficacy at human β 1 -and β 2 -adrenoceptors was only 0.1-0.2 in both studies, which did not allow quantification of potency. In human embryonic kidney (HEK) cells stably transfected with human β 3 -adrenoceptors at a density of 121-fmol/mg protein, mirabegron and isoprenaline exhibited apparent affinities of 55 nM and 34 μM, respectively, in competition radioligand binding studies, and these affinities were not substantially altered in HEK cells transfected with several naturally occurring gene variants of the receptor ).…”

“…In Chinese hamster ovary (CHO) cells stably transfected with rat β 3 -adrenoceptors, mirabegron stimulated cyclic AMP accumulation with an EC 50 of 19 nM and an efficacy of 1.0 relative to that of isoprenaline; for β 1 -adrenoceptors, an EC 50 of 610 nM and an intrinsic efficacy of 0.6 was reported, whereas for β 2 -adrenoceptors efficacy was <0.1 and potency could not be quantified (Hatanaka et al 2013b). In CHO cells transfected with cynomolgus monkey β 3 -adrenoceptors, mirabegron stimulated cAMP accumulation with an EC 50 of 32 nM and an efficacy relative to isoprenaline of 0.8; the efficacy relative to isoprenaline at β 1 -and β 2 -adrenoceptors was only 0.2 and 0.1, respectively (Someya et al 2010).…”

“…administration of mirabegron dose-dependently reduced intravesicular pressure and spontaneous bladder contractions; this was accompanied by a dose-dependent heart rate increase of up to 11 % and a mean blood pressure decrease of up to 29 % (Hatanaka et al 2013a). In rats with cerebral infarction-induced bladder dysfunction, mirabegron dosedependently increased voided volume and partly normalized it (Hatanaka et al 2013b). In rats with bladder outlet obstruction, i.v.…”

Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?

“…In organ-bath studies, mirabegron relaxed normal human urinary bladder strips [19], increased intracellular cAMP levels and activated cAMP-dependent protein kinase A [20]. This resulted in the activation and phosphorylation of myosin light-chain kinase, mediating inhibition of the Ca 2+ -calmodulin dependent interaction with actin, and a decrease in intracellular cytoplasmic Ca 2+ [21].…”