The human near‐term myometrial β3‐adrenoceptor but not the β2‐adrenoceptor is resistant to desensitisation after sustained agonist stimulation

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Abstract
1. In order to compare the beta(2)- and beta(3)-adrenoceptor (beta-AR) desensitisation process in human near-term myometrium, we examined the influence of a pretreatment of myometrial strips with either a beta(2)- or a beta(3)-AR agonist (salbutamol or SR 59119A, respectively, both at 10 microm, for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP) production induced by these agonists. 2. To assess some of the mechanisms potentially implicated in the beta-AR desensitisation process, we studied the influence of such treatment on the number of beta(2)- and beta(3)-AR binding sites, the beta(2)- and beta(3)-AR transcripts expression and the phosphodiesterase 4 (PDE4) activity. 3. Salbutamol, but not SR 59119A, concentration-response curve (CRC) was shifted by a 15 h salbutamol preincubation, with a significant difference in -log EC(20) values (6.31+/-0.13 vs 5.58+/-0.24, for control and 15 h salbutamol pretreatment, respectively, P<0.05). Neither salbutamol nor SR 59119A CRCs were modified after a 15 h preincubation with SR 59119A. 4. A 15 h exposure of myometrial strips to salbutamol significantly reduced the salbutamol-induced (0.60+/-0.26 vs 1.54+/-0.24 pmol mg(-1) protein, P<0.05), but not the SR 59119A-induced, cAMP production. No decrease in cAMP production was observed after a 15 h SR 59119A exposure. 5. A 15 h salbutamol exposure of myometrial strips significantly reduced the beta(2)- but not the beta(3)-AR binding site density, whereas no decrease in the number of beta(2)- and beta(3)-AR binding sites was observed after a 15 h SR 59119A treatment. 6. Neither PDE4 activity nor the beta(2)- and beta(3)-AR mRNA expression levels were affected by salbutamol or SR 59119A treatments. 7. Our results indicate that beta(3)-AR, but not beta(2)-AR, are resistant to the agonist-induced desensitisation. In our model, beta(2)-AR desensitisation is mediated by a decreased number of beta(2)-AR that was not explained by transcriptional regulation of the receptor.