EXPRESSION AND POSSIBLE FUNCTIONAL ROLE OF THE beta 3-ADRENOCEPTOR IN HUMAN AND RAT DETRUSOR MUSCLE

Abstract

PURPOSE: To investigate the presence of the beta3-adrenoceptor (beta3-AR) in human and rat detrusor muscle and the usefulness of beta3-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-tetrah ydro-5H-benzocyclohepton-2-yloxy]acetate monohydrochloride monohydrate, was used as a beta3-AR selective agonist. The expression of beta-AR subtypes (beta1-, beta2-, beta3-AR) mRNA was investigated in rat and human detrusor muscle by RT-PCR. Beta3-AR agonist induced cyclic AMP (cAMP) levels were measured in rat detrusor muscle strips. The relaxation response produced by a beta3-AR agonist was measured in a KCl induced tonic contraction model in rat detrusor muscle strips. The effect of a beta3-AR agonist on urinary bladder function was investigated by cystometry using a conscious rat model of urinary frequency. RESULTS: beta3-AR mRNA was substantially expressed in both rat and human detrusor muscles. The beta3-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 beta3-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 beta1-AR selective antagonist, CGP 20712A, or the beta2-AR selective antagonist, ICI 118551, suggesting that FK175 induced the relaxation via the beta3-AR. Furthermore, in the rat model, the orally administered beta3-AR agonist, FK175 (10 mg./kg.) significantly increased bladder capacity with no change of micturition pressure or threshold pressure. CONCLUSIONS: These results suggest that beta3-AR agonists may be effective in the treatment of urinary frequency.