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 β2-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 β2-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 β2-adrenoceptor antagonist ICI118551 or the β3-adrenoceptor antagonist L-748337. Fenoterol inhibited neurogenic contractions in all three species in a concentration-dependent manner with pEC50 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 (100nM) did not affect responses to fenoterol, while L-748337 (0.3–3μM) produced rightward shifts of the concentration-response curves with a pA2 value of 8.10. In mouse bladder strips ICI118551 (30nM) blocked the inhibitory effect of fenoterol (pA2=8.80), while L-748337 (10μM) inhibited the response with a pA2 of 5.79. In rat bladder ICI118551 (30nM) was without effect, while L-748,337 (10μM) inhibited the response to fenoterol with a pA2 of 5.40. From these results it is clear that fenoterol potently activates β3-adrenoceptors in human isolated urinary bladder to inhibit EFS-induced contractions. Fenoterol also activates β3-adrenoceptors in rat, but β2-adrenoceptors in mouse bladder to inhibit EFS-induced contractions.