Po-02-147 the antiarrhythmic effects of mirabegron in isolated rabbit hearts

β-3 adrenoceptor (AR) activation opposes the effects of β-1 and β-2 AR activation and rescues the effects of excessive catecholamines. BRL37344 (beta3-AR agonist) is antiarrhythmic in canine models. Mirabegron is a β-3 agonist approved by the FDA for the treatment of overactive bladder. A previous study showed that isoproterenol activates the small conductance Ca-activated K current more in female than in male ventricles. To test the hypothesis that mirabegron reduces the proarrhythmic effects of isoproterenol more effectively in female than in male ventricles. We performed optical mapping studies in 6 male and 6 female Langendorff-perfused rabbit hearts first at baseline, then sequentially after isoproterenol (ISO, 100 nM), mirabegron (1000 nM), apamin (100 nM) administration and washout in study 1. In study 2 (5 males and 5 females), we studied at baseline, then after adding mirabegron (250 nM, 500 nM, 750 nM, and 1000 nM), followed by isoproterenol and washout. All hearts underwent 10 attempts of ventricular fibrillation (VF) induction with a ventricular burst (20 Hz for 10 s) pacing at each stage of the experiment. The number of phase singularities (PSs) was determined per episode of VF (PSs/VF). In study 1, mirabegron reduced the VF inducibility (number of VF after 10 attempts) during isoproterenol infusion by an average of -2.75 (p = 0.026). When VF was induced, the PSs/VF increased by 2.4±2.1 in males and 6.6±3.3 in females (p=0.03, Figure A). Mirabegron significantly reduced the PSs/VF in both sexes and eliminated the sex differences. Apamin given after mirabegron in the presence of isoproterenol did not further change PSs/VF (p=0.63) (Figure B). The conduction velocity (CV), estimated by the inverse of the total activation time (1/s), was 16±2.7 for all hearts at baseline and 35±10 after ISO, respectively (p=0.0006). ISO did not increase CV differentially by sex (p=0.93). Mirabegron reduced the CV by an average of 15.6 (from 34±11.4 to 18±3.9) in females, which was significantly (p=0.043) more than 5.1 (from 35±8.7 to 31±9.3) in males. Figure C shows a summary of study 2. Mirabegron significantly reduced PSs/VF at 750 nM in female (p=0.015 vs. baseline) and at 1000 nM in male (p=0.033 vs. baseline) hearts. The addition of ISO did not increase PSs/VF. During ISO infusion, mirabegron reduces the CV and the PSs/VF more in females than males during VF. These data suggest that the β3 agonist is a sex-specific antiarrhythmic agent.