Beta3-adrenoceptor agonists: possible role in the treatment of overactive bladder

In the present review article, we present an overview of beta-adrenoceptor (β-AR) subtype expression at the mRNA and receptor protein levels in the human detrusor, the in vitro and in vivo bladder function of the β3-AR, the in vivo effect of β3-AR agonists on detrusor overactivity in animal models, and the available results of clinical trials of β3-AR agonists for treating overactive bladder (OAB). There is a predominant expression of β3-AR mRNA in human bladder, constituting 97% of total β-AR mRNA. Also, functionally, the relaxant response of human detrusor to catecholamines is mainly mediated through the β3-ARs. Moreover, the presence of β1-, β2-, and β3-AR mRNAs in the urothelium and suburothelial layer of human bladder has been identified. Stimulation of urothelial β-ARs results in the release of nitric oxide and an unknown substance inhibiting detrusor contractions from the urothelium. Intravenous application of CL316,243, a selective β3-AR agonist, in rats selectively inhibits mechano-sensitive Aδ-fiber activity of the primary bladder afferents. A number of selective β3-AR agonists are currently being evaluated in clinical trials for OAB with promising preliminary results. In conclusion, the β3-AR agonists are the most notable alternative class of agents to antimuscarinics in the pharmacological treatment of OAB. The β3-AR agonists act to facilitate bladder storage function probably through at least two mechanisms: first, direct inhibition of the detrusor, and second, inhibition of bladder afferent neurotransduction.