Abstract Body (Do not enter title and authors here): Background: β-3 adrenoceptor (AR) activation is antiarrhythmic in a canine model of ventricular arrhythmia. Na-K ATPase (NKA) expression is higher in female than male rats and is stimulated by β-3 agonist due to an inhibitory oxidative modification.

Objective: To test the hypothesis that mirabegron, a β-3 agonist approved by the FDA for treating overactive bladder, has more anti-fibrillatory effects in females than in male rabbit ventricles due to NKA stimulation.

Methods: We performed optical mapping studies in 6 male and 6 female Langendorff-perfused rabbit hearts at baseline, then sequentially after adding mirabegron (500 and 1000 nM), followed by ouabain (500 nM), a specific NKA blocker. All hearts underwent 10 attempts of ventricular fibrillation (VF) induction with a ventricular burst pacing (20 Hz for 10 s) at each stage of the experiment.

Results: A shows phase maps during VF. Triangles indicate PSs. Mirabegron 1000 nM significantly decreased VF inducibility (number of VF induced in the 10 attempts) from 4.8±3.2 to 2.2±2.9 (p=0.034) in females but not in males (from 4.5±2.6 to 5.0±2.8, p=0.656) (B). Consistent with our previous reports, Mirabegron 1000 nM decreased PSs/VF (number of phase singularity per VF episode) in females (from 10.5±2.7 to 2.9±3.3, p=0.010) but not in males (from 11.3±2.3 to 9.7±2.6, p=0.167). Adding ouabain did not reverse mirabegron’s effects on PSs/VF (2.4±3.9, p=0.706) in females. However, it decreased PSs/VF significantly in males (3.4±4.0, p=0.038). Mirabegron decreased conduction velocity (CV, activation time^-1, /s) in both males (from 40.3±6.5 to 30.4±5.3, p<0.001) and females (from 38.8±7.2 to 30.0±4.9, p=0.010). Adding ouabain did not further change CV in both males (31.6±8.2, p=0.434) and females (28.1± 5.3, p=0.066). Ouabain decreased APD₂₅ after mirabegron significantly (54.6±6.6 ms vs 68.4±3.4 ms in males, p=0.019; 51.4±6.9 ms vs 65.6±6.5 ms in females, p=0.049, 200 ms pacing cycle length), but did not change the APD₈₀.

Conclusion: Mirabegron reduced PSs/VF and VF inducibility more in females than males. These sex-specific antiarrhythmic effects were not affected by NKA blockade with ouabain.