Antiarrhythmic effects of mirabegron on ventricular fibrillation in Langendorff-perfused rabbit ventricles.

Abstract

β-3 adrenoceptor (AR) counteracts the β-1 and β-2 ARs and rescues the effects of excessive catecholamines. To test the hypothesis that a β-3 AR agonist (mirabegron) can reverse the effects of isoproterenol (ISO) on ventricular fibrillation (VF), we performed optical mapping studies in six male and six female Langendorff perfused rabbit hearts at baseline and after sequential administration of ISO (100 nm), mirabegron (1000 nm), apamin (100 nm) and washout (Study I). An additional six male and six female hearts were studied with mirabegron doses ranging between 250 and 1000 nm without ISO (Study II). Patch clamp studies in human embryonic kidney 293 cells were performed to determine the effect of mirabegron on the apamin-sensitive small conductance Ca²⁺ activated K⁺ current (I_KAS). Study I show that ISO increased phase singularities per VF episode (PSs/VF) in females and the dominant frequency (DF) in both sexes. Mirabegron significantly decreased PSs/VF in both sexes and significantly decreased DF in females. Study II showed no significant difference in PSs/VF between sexes at mirabegron concentrations of 250 nm and 500 nm. However, females showed significantly lower PSs/VF than males at mirabegron concentrations of 750 nm and 1000 nm. There were no differences in the DF profiles of dose-response between males and females. Mirabegron did not inhibit or activate I_KAS heterologously expressed in human embryonal kidney 293 cells. Reverse transcriptase-quantitative PCR showed no differences in β-3 AR expression between sexes. We conclude that mirabegron is antiarrhythmic, and its antiarrhythmic properties are more commonly observed in females than males. KEY POINTS: Sympathetic nerve activity activates β adrenoceptors to induce cardiac arrhythmia. Among the β adrenoceptors, β-3 counteracts the effects of β-1 and β-2. Mirabegron is an US Food and Drug Administration (FDA)-approved β-3 agonist that does not by itself block cardiac ionic currents or prolong the QT interval. We showed that mirabegron significantly prevents wave breaks and reduces the dominant frequency of ventricular fibrillation. These effects are more prominent in female than in male rabbit ventricles. Because the FDA approves mirabegron for human use, its antiarrhythmic effects can be readily tested in humans.