Combination therapy with β3 -adrenoceptor agonists and muscarinic acetylcholine receptor antagonists: Efficacy in rats with bladder overactivity

Objective: To investigate the efficacy of combination therapy of a selective β3 -adrenoceptor agonist (mirabegron) and muscarinic acetylcholine receptor antagonists (a selective muscarinic acetylcholine receptor2 antagonist: methoctramine hemihydrate or a selective muscarinic acetylcholine receptor3 antagonist; 4-DAMP) compared with monotherapy of either agent in rats with oxotremorine methiodide (a non-selective muscarinic acetylcholine receptor agonist)-induced bladder overactivity.

Methods: Cystometry was carried out in conscious female rats with intravesical instillation of oxotremorine methiodide (200 μmol/L). Either mirabegron (0.3-3 mg/kg), methoctramine (0.1-1 mg/kg) or 4-DAMP (0.03-0.3 mg/kg) was cumulatively applied intravenously. Also, the effects of combined application of mirabegron (3 mg/kg) plus methoctramine (1 mg/kg) or 4-DAMP (0.3 mg/kg) on cystometric parameters were compared with those of single-agent monotherapy.

Results: Intravesical instillation of oxotremorine methiodide induced bladder overactivity, as evidenced by decreases in threshold pressure and bladder capacity. In oxotremorine methiodide-treated rats, single application of mirabegron (1, 3 mg/kg), methoctramine (0.3, 1 mg/kg) or 4-DAMP (0.1, 0.3 mg/kg) decreased baseline pressure and increased bladder capacity. In addition, reductions in threshold pressure and maximal voiding pressure were also seen after the administration of 4-DAMP (0.3 mg/kg). The combined treatment of mirabegron plus 4-DAMP induced a larger increase in bladder capacity compared with monotherapy of either drug, whereas there were no significant changes in cystometric parameters between the combination therapy of mirabegron plus methoctramine and monotherapy of either drug.

Conclusion: These results suggest that the combination therapy of β3 -adrenoceptor agonists plus muscarinic acetylcholine receptor3 antagonists is more effective compared with monotherapy for the treatment of bladder overactivity. In contrast, the efficacy of β3 -adrenoceptor agonists might not be increased by the addition of muscarinic acetylcholine receptor2 antagonists.