The subtypes of muscarinic receptors for neurogenic bladder contraction in rats

Abstract We evaluated in vivo functional selectivity profiles for muscarinic M 2 and M 3 subtypes of four muscarinic antagonists: Compound A (a novel muscarinic receptor antagonist with M 2 -sparing antagonistic activity), darifenacin, (a muscarinic M 3 receptor antagonist); methoctramine (a muscarinic M 2 receptor antagonist) and tolterodine (a nonselective muscarinic receptor antagonist), and compared the inhibition potency on distention-induced bladder contraction in rats. In an in vivo functional study, Compound A (0.03–10 mg/kg, i.v.) showed antimuscarinic activity with high selectivity for M 3 (salivation) over M 2 (bradycardia) (>100-fold). Darifenacin (0.01–0.3 mg/kg, i.v.) showed only slight selectivity for M 3 over M 2 (3.7-fold). Methoctramine (0.003–1 mg/kg, i.v.) showed the reverse selectivity profile (0.077-fold). Tolterodine (0.003–0.3 mg/kg, i.v.) showed less selectivity (1.2-fold). Compound A at M 3 inhibitory doses (0.1 and 0.3 mg/kg, i.v.) showed inhibition in a distention-induced neurogenic bladder contraction model, and its maximal inhibitory effects were about 60% at an even higher dose (3 mg/kg). Methoctramine at M 2 inhibitory doses (0.03 and 0.1 mg/kg, i.v.) did not significantly affect distention-induced bladder contraction. When tolterodine and darifenacin caused inhibition of distention-induced bladder contraction, its maximal inhibitory effects were similar to that of Compound A. Therefore, these findings suggest that Compound A would be an excellent pharmacological tool to give a better understanding of which subtypes of muscarinic receptors act in bladder function so far, and muscarinic M 3 , but not M 2 , receptors mainly mediate the cholinergic component of distention-induced bladder contraction.