Possible Involvement of β₁-Adrenoceptors in the Positive Chronotropic Effects of Mirabegron

Mirabegron, a β₃-adrenoceptor agonist used to treat overactive bladder, is associated with increased heart rate; however, the mechanism underlying its cardiac effect remains unclear. In this study, we investigated the β-adrenoceptor subtypes that are involved in the chronotropic effects of mirabegron in mouse and guinea pig atria. Mirabegron (0.03-10 μM) produced concentration-dependent positive chronotropic effects in both species, with maximum effects of 75.9% in mice and 27.7% in guinea pigs. Isoproterenol (0.1-100 nM), a nonselective β-adrenoceptor agonist, dobutamine (0.001-100 μM), a β₁-adrenoceptor agonist, and salbutamol (0.001-100 μM), a β₂-adrenoceptor agonist, induced concentration-dependent positive chronotropic effects, with the potency order of isoproterenol > dobutamine > mirabegron ≥ salbutamol in mice, and isoproterenol > dobutamine ≥ salbutamol > mirabegron in guinea pigs. Mirabegron-induced positive chronotropic effects were unaffected by 0.1% dimethyl sulfoxide in the mouse atria, but non-competitively antagonized by the selective β₃-adrenoceptor antagonist L748337 (100-1000 nM), with the slope of the Schild plot being 0.65. The selective β₂-adrenoceptor antagonist ICI118551 (30 nM) attenuated the positive chronotropic effects of mirabegron, producing a 3-fold rightward shift in the concentration-response curve. Conversely, the selective β₁-adrenoceptor antagonist CGP20172A (0.03-3 nM) strongly and non-competitively antagonized mirabegron-induced positive chronotropic effects in mouse and guinea pig atria. These results suggest that the positive chronotropic effects of mirabegron are primarily mediated through β₁-adrenoceptors, with minimal or no involvement of β₂- and β₃-adrenoceptors.