title: Fenoterol functionally activates the β₃-adrenoceptor in human urinary bladder, comparison with rat and mouse: implications for drug discovery.
abstract: Fenoterol has been reported to be a potent and selective β(2)-adrenoceptor agonist and is currently used clinically to treat asthma. Electrical field stimulation (EFS) of isolated urinary bladder mimics the voiding contraction by stimulating parasympathetic nerves, resulting in neurogenic contractions. To determine if stimulation of β(2)-adrenoceptors can inhibit this response, fenoterol was tested against EFS-induced contractions in human isolated urinary bladder and compared with mouse and rat. Bladder strips were mounted in organ baths and reproducible contractions induced by EFS. Fenoterol was added cumulatively in the presence of the β(2)-adrenoceptor antagonist ICI118551 or the β(3)-adrenoceptor antagonist L-748337. Fenoterol inhibited neurogenic contractions in all three species in a concentration-dependent manner with pEC(50) values of 6.66 ± 0.11, 6.86 ± 0.06 and 5.71 ± 0.1 in human, mouse and rat respectively. In human bladder strips ICI118551 (100 nM) did not affect responses to fenoterol, while L-748337 (0.3-3 μM) produced rightward shifts of the concentration-response curves with a pA(2) value of 8.10. In mouse bladder strips ICI118551 (30 nM) blocked the inhibitory effect of fenoterol (pA(2)=8.80), while L-748337 (10 μM) inhibited the response with a pA(2) of 5.79. In rat bladder ICI118551 (30 nM) was without effect, while L-748,337 (10 μM) inhibited the response to fenoterol with a pA(2) of 5.40. From these results it is clear that fenoterol potently activates β(3)-adrenoceptors in human isolated urinary bladder to inhibit EFS-induced contractions. Fenoterol also activates β(3)-adrenoceptors in rat, but β(2)-adrenoceptors in mouse bladder to inhibit EFS-induced contractions.
authors: UROsphere, Faculté des Sciences Pharmaceutiques, 35, Chemin des Maraîchers Toulouse Cedex 09, 31062 Toulouse, France.
authors: Stefano
authors: S
authors: Palea
authors: Moèz
authors: M
authors: Rekik
authors: Céline
authors: C
authors: Rouget
authors: Philippe
authors: P
authors: Camparo
authors: Henri
authors: H
authors: Botto
authors: Pascal
authors: P
authors: Rischmann
authors: Philippe
authors: P
authors: Lluel
authors: Timothy D
authors: TD
authors: Westfall
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000368:Aged; D000818:Animals; D055808:Drug Discovery; D004558:Electric Stimulation; D005260:Female; D005280:Fenoterol / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013045:Species Specificity; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D022702:Receptors, Adrenergic, beta-3; D005280:Fenoterol