Beta3-adrenoceptors in human detrusor muscle.

The detrusor muscle contains beta-adrenoceptors (beta-AR), and 2 subtypes-beta1-AR and beta2-AR-have been identified in most species. Although beta2-AR has an important role in muscle relaxation via activation of adenylate cyclase, evidence suggests that a third subtype, beta3-AR, which is implicated in metabolic functions of endogenous catecholamines, mediates relaxation of human detrusor muscle. There is a predominant expression of beta3-AR messenger RNA (mRNA) in human bladder tissue, with 97% of total beta-AR mRNA being represented by the beta3-AR subtype and only 1.5% and 1.4% by the beta1-AR and beta2-AR subtypes, respectively. Functionally, selective beta3-AR agonists relax human isolated detrusor, whereas selective beta1-AR/beta2-AR agonists do not. Isoproterenol-induced relaxation is inhibited by selective beta3-AR antagonists but not by selective beta1-AR or beta2-AR antagonists. In animal models, beta3-AR agonists increase bladder capacity and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of beta3-AR agonists as therapy for overactive bladder, clinical trials of beta3-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 beta3-AR, identified by screening techniques using cell lines transfected with the human beta1-AR, beta2-AR, and beta3-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 beta3-AR gene, which may be a useful genetic marker, evidence points toward beta3-AR being a therapeutic target for treatment of overactive bladder disorder.