The beta(3)-adrenoceptor agonist mirabegron …

Mo, W. L., et al. (2017). "The beta(3)-adrenoceptor agonist mirabegron increases human atrial force through beta(1)-adrenoceptors: an indirect mechanism?" British Journal of Pharmacology 174(16): 2706-2715.

BACKGROUND AND PURPOSE Mirabegron has been classified as a beta(3)-adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of beta-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers. EXPERIMENTAL APPROACH Right atrial trabeculae, from non-failing hearts, were paced and contractile force measured at 37 degrees C. Single concentrations of mirabegron were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), beta(3) (L-748,337), beta(1) (CGP 20712A), beta 2 (ICI 118,551) -adrenoceptor antagonists, neuronal uptake inhibitors desipramine or phenoxybenzamine. KEY RESULTS Mirabegron significantly increased contractile force in human right atrium (1 mu M, 7.6 +/- 2.6%, n = 7; 10 mu M, 10.2 +/- 1.5%, n = 22 compared with (-)-isoprenaline P < 0.05). In the presence of IBMX, mirabegron (10 mu M) caused a greater contraction. L-748,337 (100 nM) had no effect on the increase in contractile force caused by mirabegron (10 mu M). In contrast, mirabegron (10 mu M) reduced contractile force in the presence of CGP 20712A, which was not affected by L-748,337 (100 nM) or ICI 118,551 (50 nM). Mirabegron (10 mu M) also reduced contractile force in the presence of desipramine or phenoxybenzamine. CONCLUSIONS AND IMPLICATIONS Mirabegron increases human atrial force through beta(1)-but not beta(3)-adrenoceptors. Desipramine and phenoxybenzamine block neuronal uptake and conceivably prevent mirabegron from releasing noradrenaline. A non-specific cardiodepressant effect is not mediated through beta(3) (or beta(2))-adrenoceptors, consistent with lack of beta(3)-adrenoceptor function on human atrial contractility.

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Characterizing preclinical sub-phenotypic models of acute respiratory distress syndrome: An experimental ovine study