β3-adrenoceptors in human detrusor muscle

The detrusor muscle contains beta-adrenoceptors (beta-AR), and 2 subtypes-beta(1)-AR and beta(2)-AR-have been identified in most species. Although beta(2)-AR has an important role in muscle relaxation via activation of adenylate cyclase, evidence suggests that a third subtype beta(3)-AR, which is implicated in metabolic functions of endogenous catecholamines, mediates relaxation of human detrusor muscle. There is a predominant expression Of beta(3)-AR messenger RNA (mRNA) in human bladder tissue, with 97% of total beta-AR mRNA being represented by the beta(3)-AR subtype and only 1.5% and 1.4% by the beta(1)-AR and beta(2)-AR subtypes, respectively, Functionally, selective beta(3)-AR agonists relax human isolated detrusor, whereas selective beta(1)-AR/beta(2)-AR agonists do not. Isoproterenol-induced relaxation is inhibited by selective beta(3)-AR antagonists but not by selective beta(1)-AR or beta(2)-AR antagonists. In animal models, beta(3)-AR agonists increase bladder capacity and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of beta(3)-AR agonists as therapy for overactive bladder, clinical trials Of beta(3)-AR agonists identified in animal models as antiobesity agents indicate side effects of tremor and tachycardia. Development of compounds with high selectivity for the human beta(3)-AR, identified by screening techniques using cell lines transfected with the human beta(1)-AR, beta(2)-AR, and beta(3)-AR genes, may mitigate such problems. Together with the preliminary finding that 49% (21 of 43) of patients with idiopathic detrusor instability have a tryptophan 64 arginine mutation of the beta(3)-AR gene, which may be a useful genetic marker, evidence points toward beta(3)-AR being a therapeutic target for treatment of overactive bladder disorder.