Fenoterol functionally activates the β3-adrenoceptor in human urinary bladder, comparison with rat and mouse: Implications for drug discovery

Fenoterol has been reported to be a potent and selective beta(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 beta(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 beta(2)-adrenoceptor antagonist ICI118,551 or the beta(3)-adrenoceptor antagonist L-748,337. 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 ICI118,551 (100nM) did not affect responses to fenoterol, while L-748,337 (0.3-3 mu M) produced rightward shifts of the concentration-response curves with a pA(2) value of 8.10. In mouse bladder strips ICI 118,551 (30nM) blocked the inhibitory effect of fenoterol (pA(2)=8.80), while L-748,337 (10 mu M) inhibited the response with a pA(2) of 5.79. In rat bladder ICI 118,551 (30nM) was without effect, while L-748,337 (10 mu M) inhibited the response to fenoterol with a pA(2) of 5.40. From these results it is clear that fenoterol potently activates beta(3)-adrenoceptors in human isolated urinary bladder to inhibit EFS-induced contractions. Fenoterol also activates beta(3)-adrenoceptors in rat, but beta(2)-adrenoceptors in mouse bladder to inhibit EFS-induced contractions. (C) 2012 Elsevier B.V. All rights reserved.