Differential Roles of M2 and M3 Muscarinic Receptor Subtypes in Modulation of Bladder Afferent Activity in Rats

Abstract

To investigate the effects of various muscarinic acetylcholine receptor (mAChR) antagonists, including selective M2 and M3 mAChR antagonists, on bladder overactivity. It has been proposed that the urothelium modulates the activity of bladder afferent pathways. However, the differential roles of mAChR subtypes in local bladder afferent activation remain unclear. Cystometry was performed in urethane-anesthetized female rats. We examined the effects of intravesical administration of antimuscarinic agents (nonselective mAChR antagonists: atropine sulfate, tolterodine tartrate, and propiverine hydrochloride; M2-selective antagonists: dimethindene maleate and methoctramine hemihydrate; M3-selective antagonists: darifenacin hydrobromide and 4-DAMP) on bladder overactivity induced by oxotremorine-M (oxo-M; nonselective mAChR agonist). Intravesical administration of oxo-M (200 microM) elicited bladder overactivity as evidenced by decreased intercontraction interval, bladder capacity, and pressure threshold. These effects were blocked by intravesical administration of nonselective or M2-selective antagonists (30-60 microM), whereas M3-selective antagonists (150 microM) did not suppress the overactivity. When instilled intravesically by itself, none of the antimuscarinic agents (nonselective, M2-selective or M3-selective antagonists) affected any cystometric parameters. The M2 mAChR subtype plays an important role in the local cholinergic modulation of bladder afferent activity that contributes to bladder overactivity in normal rats. Therefore, it is expected that antimuscarinic agents that have antagonistic activity against M2 mAChR can be more beneficial for the treatment of patients with overactive bladder if enhanced acetylcholine mechanisms are involved in pathogenesis of overactive bladder.