β₃‐Adrenoceptors in urinary bladder

Abstract

The beta-adrenoceptor (AR) is currently classified into beta(1), beta(2), and beta(3) subtypes. A third subtype, beta(3)-AR, was first identified in adipose tissue, but has also been identified in smooth muscle tissue, particularly in the gastrointestinal tract and urinary bladder smooth muscle. There is a predominant expression of beta(3)-AR messenger RNA (mRNA) in human bladder, 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. Moreover, the presence of beta(1)-, beta(2)-, and beta(3)-AR mRNAs in the urothelium of human bladder has been identified. The distribution of beta-AR subtypes mediating detrusor muscle relaxation is species dependent, the predominant subtype being the beta(3)-AR in humans. Recent studies have suggested that cAMP-dependent routes are not exclusive mechanisms triggering the beta-AR-mediated relaxation of smooth muscle. It has been demonstrated in rats detrusor muscle that cAMP plays a greater role in beta-adrenergic relaxation against basal tone than against KCl-induced tone and that conversely calcium-activated K(+) channels (BKca channels) play a greater role under the latter circumstances. In rat models, beta(3)-AR agonists increase bladder capacity without influencing bladder contraction 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 (OAB), pharmacological differences exist between rat and human beta(3)-ARs. 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)-, beta(2)-, and beta(3)-AR genes, may mitigate against such problems. The association between the tryptophan 64 arginine polymorphism in the beta(3)-AR gene and idiopathic OAB is discussed.

Effects of β3-Adrenergic Receptor Activation on Rat Urinary Bladder Hyperactivity Induced by Ovariectomy

“…␤ 3 AR agonists also relaxed rat bladder smooth muscle strips (Fujimura et al, 1999;Longhurst and Levendusky, 1999;Woods et al, 2001;Takeda et al, 2003). Relaxation of rat detrusor can be mediated by all ␤ARs (Yamaguchi and Chapple, 2007). In tissues where ␤ 2 ARs and ␤ 3 ARs are coexpressed, the ␤ 2 /␤ 3 receptor heterodimer can mediate unique signals (Breit et al, 2004).…”

“…Three subtypes of ␤ARs, ␤ 1 AR, ␤ 2 AR, and ␤ 3 AR, are expressed in bladder of several species, including human and rat (Yamaguchi and Chapple, 2007). ␤ 3 ARs, which are considered the predominant subtype in human bladder, are coupled to excitatory G s and inhibitory G i proteins (Vrydag and Michel, 2007).…”

“…Several ␤ 3 AR agonists are currently in clinical trials for the treatment of OAB (Yamaguchi and Chapple, 2007). Although these trials enroll patients of both genders, the bladders of postmenopausal women may be uniquely influenced by hormonal status.…”

Urothelial Signaling

“…It has been shown that urothelial-derived NO can be released in response to mechanical as well as chemical stimulation and may either facilitate or inhibit the activity of bladder afferent nerves conveying bladder sensation (18,42). In this regard, activation of urothelial receptors and release of inhibitory mediators may explain, in part, the mechanism of action for therapies (e.g., ␤ 3 -AR agonists) in treatment of bladder disorders such as the overactive bladder (OAB) (137,283,301).…”

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology and Pharmacotherapy of Overactive Bladder

“…The effective alternative class of agents to the antimuscarinics with proven efficacy and acceptable tolerability are the β 3 -adrenoceptor agonists (35). The detrusor muscle containing β -ARs and three subtypes ( β 1 , β 2 , and β 3 ) have been identified in most species (36,37).…”