Expression and possible functional role of the β3-adrenoceptor in human and rat detrusor muscle

Purpose: To investigate the presence of the beta 3-adrenoceptor (beta 3-AR) in human and rat detrusor muscle and the usefulness of beta 3-AR agonists as drugs for the treatment of urinary frequency. Materials and Methods: FK175, ethyl [(S)-8-[(R)-2-(3-chlorophenyl)-2-hydroxyethylamino]- 6,7,8,9-tetrahydro-5H-benzocyclohepton-2-yloyx]acetate monohydrochloride monohydrate, was used as a beta 3-AR selective agonist. The expression of beta-AR subtypes (beta 1-, beta 2-, beta 3-AR) mRNA was investigated in rat and human detrusor muscle by RT-PCR. beta 3-AR agonist induced cyclic AMP (cAMP) levels were measured in rat detrusor muscle strips. The relaxation response produced by a beta 3-AR agonist was measured in a KCl induced tonic contraction model in rat detrusor muscle strips. The effect of a beta 3-AR agonist on urinary bladder function was investigated by cystometry using a conscious rat model of urinary frequency. Results: beta 3-AR mRNA was substantially expressed in both rat and human detrusor muscles. The beta 3-AR agonist, FK175 (10(-7) M), increased the cAMP level by 30% in rat detrusor muscle. In isolated rat detrusor muscle strips contracted with KCl, the beta 3-AR agonist, FK175 (10(-8) to 10(-4) M), produced a concentration-dependent relaxation. Moreover, although the relaxation induced with FK175 was blocked by the non-selective beta-AR antagonist, bupranolol, it was unaffected by ether the beta 1-AR selective antagonist, CGP 20712A, or the beta 2-AR selective antagonist, ICI 118551, suggesting that FK175 induced the relaxation via the beta 3-AR. Furthermore, in the rat model, the orally administered beta 3-AR agonist, FK175 (10 mg./kg.) significantly increased bladder capacity with no change of micturition pressure or threshold pressure. Conclusions: These results suggest that beta 3-AR, agonists may be effective in the treatment of urinary frequency.