Excitatory effect of acotiamide on rat and human bladder: Implications for underactive bladder treatment

To evaluate whether approved gastroprokinetic agent, acotiamide exerts a direct excitatory effect on bladder to help explain the reported meaningful reduction of post-void residual urine volume (PVR) in detrusor underactivity (DU) patients after thrice daily oral intake of acotiamide 100 mg for 2 weeks.

Effect of acotiamide [1-16 μM] was assessed on nerve-mediated contractions evoked by electrical field stimulation (EFS) for 5 s with 5 ms pulse trains of 10 V in longitudinal, mucosa intact rat and human bladder strips to construct frequency response curve (1-32 Hz) and repeat 10 Hz stimulation at 60s interval. Effect of acotiamide 2 μM on spontaneous and carbachol evoked contractions was also assessed.

Acotiamide 2 μM significantly enhanced the Atropine and Tetrodotoxin (TTX)-sensitive EFS evoked contractions of rat and human bladder at 8-32 Hz (Two-way ANOVA followed Sidak's multiple comparison; *p < 0.01) and on repeat 10 Hz stimulation (Paired Student's t-test; *p < 0.05), while producing a modest effect on the spontaneous contractions and a negligible effect on the carbachol evoked contractions.

Enhancement of TTX-sensitive evoked contractions of rat and human bladder by acotiamide is consistent with the enhancement of excitatory neuro-effector transmission mainly through prejunctional mechanisms. Findings highlight immense therapeutic potential of antimuscarinics with low M3 receptor affinity like acotiamide in Underactive bladder (UAB)/DU treatment.