Effects of 138–355, a β3-adrenoceptor selective agonist, on relaxation of the human detrusor muscle in vitro

Aims β-adrenoceptors are the predominant β-adrenoceptor subtype present in the bladder and urethra. This study investigates the effects of 138–355, an active-metabolite of TT-138 and β3-adrenoceptor agonist, on relaxation of the human detrusor in vitro. Methods Tumor-free tissue samples of human bladder muscle from 39 patients undergoing total cystectomy due to bladder cancer were obtained, and the mucosa and serosa were removed. Tissues were mounted in 5 or 10 ml organ baths containing Krebs solution, which was gassed with 95% O2 and 5% CO2. Resting tension of 1 g was obtained. When the contraction had stabilized, increasing concentrations of β adrenoceptor agonists (non-selective, isoprenaline; β2-selective, clenbuterol; β3-selective, 138–355 and BRL37344) and propiverine (a non-selective anti-muscarinic antagonist) were added cumulatively and concentration-relaxation curves (CRCs) were obtained. CRCs to 138–355 were obtained in the absence and presence of SR59230A, a β3-selective antagonist, and antagonist affinity values (pA2) were calculated from the Schild plot. Results Isoproterenol, clenbuterol, 138–355 and BRL37344 concentration-dependently relaxed isolated human urinary bladder strips with pEC50 value being 6.76±0.17, 5.23±0.22, 5.80±0.26 and 5.90±0.28, respectively. Following antagonist assay, it was observed that concentration-relaxation curves to 138–355 was competitively antagonized by β3- adrenoceptor antagonist, SR59230A, with a pA2 value of 7.01±0.45 and with a Schild slope of 0.72±0.07. Conclusions Involvement of the β3-adrenoceptor appears to be greater than that of the β3-adrenoceptor for relaxations of the human bladder. The relaxation response of 138–355 appears to be mediated via the β3-adrenoceptor stimulation. Neurourol. Urodynam. 25:815–819, 2006. © 2006 Wiley-Liss, Inc.