Tools to study beta3-adrenoceptors

Beta(3)-adrenoceptors mediate some of the effects of catecholamines on tissues such as blood vessels or the urinary bladder and are putative targets for the treatment of diseases such as the overactive bladder syndrome. Progress in the understanding of the presence, function, and regulation of beta(3)-adrenoceptors has been hampered by a lack of highly specific tools. "Classical" beta(3)-adrenoceptor agonists such as BRL 37,344 [(R*, R*)-(+/-)-4[2-[(3-chlorophenyl)-2-hydroxyethyl) amino] propyl] phenoxyacetic acid] and CGP 12,177 [(+/-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one] are only partial agonists in many settings, have limited selectivity over other beta-adrenoceptor subtypes, and may additionally act on receptors other than beta-adrenoceptors. More efficacious and more selective agonists have been reported and, in some cases, are in clinical development but are not widely available for experimental studies. The widely used antagonist SR 59,230 [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxalate] is not selective for beta(3)-adrenoceptors, at least in humans, and may actually be a partial agonist. Radioligands, which are suitable either for the selective labeling of beta(3)-adrenoceptors or for the nonselective labeling of all beta-adrenoceptor subtypes, are also missing. beta(3)- and beta(1)/beta(2) double knockout mice have been reported, but their usefulness for extrapolations in humans is questionable based upon major differences between humans and rodents with regard to the ligand recognition and expression profiles of beta(3)-adrenoceptors. While the common availability of more selective agonists and antagonists at the beta(3)-adrenoceptor is urgently awaited, the limitations of the currently available tools need to be considered in studies of beta(3)-adrenoceptor for the time bein

α(1)-, α(2)- and β-adrenoceptors in the urinary bladder, urethra and prostate

1. We have systematically reviewed the presence, functional responses and regulation of α(1)-, α(2)- and β-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes. 2. α(1)-Adrenoceptors are only poorly expressed and play a limited functional role in the detrusor. α(1)-Adrenoceptors, particularly their α(1A)-subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates. α(1)-Adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate. 3. α(2)-Adrenoceptors, mainly their α(2A)-subtype, are expressed in bladder, urethra and prostate. They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans. Their overall post-junctional function in the lower urinary tract remains largely unclear. 4. β-Adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate. The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the β(3)- and β(2)-subtypes are important in the human bladder and urethra, respectively. β(3)-Adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder. 5. We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence. Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment