Korean J Urol.  2010 Dec;51(12):811-818.

Beta3-Adrenoceptor Agonists: Possible Role in the Treatment of Overactive Bladder

• Igawa Y
• Aizawa N
• Homma Y

Abstract

In the present review article, we present an overview of beta-adrenoceptor (beta-AR) subtype expression at the mRNA and receptor protein levels in the human detrusor, the in vitro and in vivo bladder function of the beta3-AR, the in vivo effect of beta3-AR agonists on detrusor overactivity in animal models, and the available results of clinical trials of beta3-AR agonists for treating overactive bladder (OAB). There is a predominant expression of beta3-AR mRNA in human bladder, constituting 97% of total beta-AR mRNA. Also, functionally, the relaxant response of human detrusor to catecholamines is mainly mediated through the beta3-ARs. Moreover, the presence of beta1-, beta2-, and beta3-AR mRNAs in the urothelium and suburothelial layer of human bladder has been identified. Stimulation of urothelial beta-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 beta3-AR agonist, in rats selectively inhibits mechano-sensitive Adelta-fiber activity of the primary bladder afferents. A number of selective beta3-AR agonists are currently being evaluated in clinical trials for OAB with promising preliminary results. In conclusion, the beta3-AR agonists are the most notable alternative class of agents to antimuscarinics in the pharmacological treatment of OAB. The beta3-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.

Keyword

Adrenergic beta-agonists; Afferent pathways; Urinary bladder, overactive

MeSH Terms

Adrenergic beta-Agonists
Afferent Pathways
Animals
Catecholamines
Contracts
Dioxoles
Humans
Models, Animal
Muscarinic Antagonists
Nitric Oxide
Rats
RNA, Messenger
Urinary Bladder
Urinary Bladder, Overactive
Urothelium
Adrenergic beta-Agonists
Catecholamines
Dioxoles
Muscarinic Antagonists
Nitric Oxide
RNA, Messenger

Figure

• 

  FIG. 1 Primary structure of the human beta3-adrenoceptor. Taken with permission from Ursino et al (2009) [2]. PKA: cAMP-dependent protein kinase, β-ARK: beta-adrenergic receptor kinase.

• 

  FIG. 2 Inhibition of isoprenaline-induced relaxation of human bladder detrusor by the β1-AR antagonist CGP 20,712, the β2-AR antagonist ICI 118,551, and the β3-AR antagonist SR 58,894. Taken with permission from Igawa et al (1999) [14].

• 

  FIG. 3 Relaxing effect of isoproterenol, YM178, and CGP-12177A in rat (A) and human (B) bladder strips precontracted with carbachol. Taken with permission from Takasu et al (2007) [30].

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