Effects of 138-355, a beta3-adrenoceptor selective agonist, on relaxation of the human detrusor muscle in vitro.
OBJECTIVE
Beta-adrenoceptors are the predominant beta-adrenoceptor subtype present in the bladder and urethra. This study investigates the effects of 138-355, an active-metabolite of TT-138 and beta(3)-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% O(2) and 5% CO(2). Resting tension of 1 g was obtained. When the contraction had stabilized, increasing concentrations of beta adrenoceptor agonists (non-selective, isoprenaline; beta(2)-selective, clenbuterol; beta(3)-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 beta(3)-selective antagonist, and antagonist affinity values (pA(2)) were calculated from the Schild plot.


RESULTS
Isoproterenol, clenbuterol, 138-355 and BRL37344 concentration-dependently relaxed isolated human urinary bladder strips with pEC(50) 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 beta(3)- adrenoceptor antagonist, SR59230A, with a pA(2) value of 7.01+/-0.45 and with a Schild slope of 0.72+/-0.07.


CONCLUSIONS
Involvement of the beta(3)-adrenoceptor appears to be greater than that of the beta(3)-adrenoceptor for relaxations of the human bladder. The relaxation response of 138-355 appears to be mediated via the beta(3)-adrenoceptor stimulation.
Yamanishi
Tomonori
T
Department of Urology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi, 321-0293, Japan. yamanish@dokkyomed.ac.jp
Yasuda
Kosaku
K
Kitahara
Satoshi
S
Nakai
Hideo
H
Yoshida
Ken-Ichiro
K
Iizuka
Hiroyuki
H
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002976:Clenbuterol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010642:Phenoxyacetates / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects*
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; C119908:GS 332; D018727:Muscarinic Antagonists; D010642:Phenoxyacetates; D011433:Propranolol; D007545:Isoproterenol; D000420:Albuterol; D002976:Clenbuterol