Effects of the combination of vibegron and imidafenacin on bladder function in urethane-anesthetized rats

Abstract

The combination of a β3-adrenoceptor agonist and an antimuscarinic agent was revealed to be more effective than monotherapy for patients with overactive bladder and in animal models. However, its influence on voiding functions has not been well documented. Therefore, during intermittent-cystometry, we studied the effects of vibegron (a novel β3-adrenoceptor agonist) and imidafenacin (an antimuscarinic agent) alone to determine their dose levels for the combination study. Then, the effects of the combination on voiding functions were investigated in urethane-anesthetized rats (1.0 g/kg s.c.). Independently, vibegron (0.3–3 mg/kg, i.v.) and imidafenacin (0.001 and 0.003 mg/kg, i.v.) dose-dependently increased bladder capacity and voided volume, without affecting voiding functions such as residual volume, voiding efficiency, and micturition pressure. However, vibegron also increased bladder compliance. The combination of vibegron (3 mg/kg) and imidafenacin (0.003 mg/kg) significantly increased bladder capacity and voided volume when compared to those with monotherapy using each individually. The combination did not change residual volume, voiding efficiency, and micturition pressure, compared to those in the vehicle group. We identified no responses in resiniferatoxin (RTX)-treated rats, as opposed to those identified after administering vibegron (3 mg/kg), imidafenacin (0.003 mg/kg), or both to non-RTX-treated rats. These outcomes might have resulted from the combination of the increased effect of vibegron on bladder compliance and the inhibitory effect of both vibegron and imidafenacin on the activation of bladder afferent nerves.