Attenuation of Non‐neuronal Adenosin Triphosphate Release from Human Bladder Mucosa by Antimuscarinic Agents

Abstract

Objectives: To clarify the contribution of mucosal muscarinic receptors to bladder function, we investigated the effects of various antimuscarinic drugs on stretch‐induced non‐neuronal adenosin triphosphate (ATP) release in human bladder.Methods: Human bladders were obtained from 17 patients. Bladder strips with and without mucosa were suspended in organ baths. A microdialysis probe was inserted into the strip, Ringer's solution was perfused into the probe, and dialysate was collected under tetrodotoxin pretreatment. The amount of ATP released in dialysate was measured by luciferin‐luciferase assay. The effects of various antimuscarinic drugs on non‐neuronal ATP release were evaluated.Results: Non‐neuronal ATP release from bladder strips without mucosa was approximately 10% of that from strips with mucosa. Non‐neuronal ATP release was significantly inhibited by pretreatment with nifedipine or in Ca2+‐free medium. Both methoctramine (M2 receptor selective antagonist) and 4‐diphenyl‐acetoxy‐N‐methylpiperidine methiodide (4‐DAMP [M3 receptor selective antagonist]) significantly inhibited release. However, M1 receptor selective antagonist (pirenzepine) did not have a significant effect on release. Oxybutynin, propiverine, tolterodine and solifenacin caused concentration‐dependent inhibition in non‐neuronal ATP release. The rank order of the maximum inhibition rate was propiverine ≥ solifenacin ≥ tolterodine ≥ oxybutynin. Solifenacin showed an inhibitory effect at a lower concentration compared to other drugs.Conclusion: The data suggest that human bladder mucosa is a main source of stretch‐induced non‐neuronal ATP release, and that stimulation of M2 and M3 receptor subtypes of mucosa partly contributes to non‐neuronal ATP release. Various antimuscarinic drugs used for the treatment of overactive bladder may have different inhibitory effects on non‐neuronal ATP release.