The human near‐term myometrial β3‐adrenoceptor but not the β2‐adrenoceptor is resistant to desensitisation after sustained agonist stimulation
C Rouget, M Breuiller‐Fouché… - British journal of …, 2004 - Wiley Online Library
C Rouget, M Breuiller‐Fouché, FJ Mercier, MJ Leroy, C Loustalot, E Naline, R Frydman…
British journal of pharmacology, 2004•Wiley Online LibraryIn order to compare the β2‐and β3‐adrenoceptor (β‐AR) desensitisation process in human
near‐term myometrium, we examined the influence of a pretreatment of myometrial strips
with either a β2‐or a β3‐AR agonist (salbutamol or SR 59119A, respectively, both at 10 μm,
for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP)
production induced by these agonists. To assess some of the mechanisms potentially
implicated in the β‐AR desensitisation process, we studied the influence of such treatment …
near‐term myometrium, we examined the influence of a pretreatment of myometrial strips
with either a β2‐or a β3‐AR agonist (salbutamol or SR 59119A, respectively, both at 10 μm,
for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP)
production induced by these agonists. To assess some of the mechanisms potentially
implicated in the β‐AR desensitisation process, we studied the influence of such treatment …
- In order to compare the β2‐ and β3‐adrenoceptor (β‐AR) desensitisation process in human near‐term myometrium, we examined the influence of a pretreatment of myometrial strips with either a β2‐ or a β3‐AR agonist (salbutamol or SR 59119A, respectively, both at 10 μM, for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP) production induced by these agonists.
- To assess some of the mechanisms potentially implicated in the β‐AR desensitisation process, we studied the influence of such treatment on the number of β2‐ and β3‐AR binding sites, the β2‐ and β3‐AR transcripts expression and the phosphodiesterase 4 (PDE4) activity.
- Salbutamol, but not SR 59119A, concentration–response curve (CRC) was shifted by a 15 h salbutamol preincubation, with a significant difference in −log EC20 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.
- 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.
- A 15 h salbutamol exposure of myometrial strips significantly reduced the β2‐ but not the β3‐AR binding site density, whereas no decrease in the number of β2‐ and β3‐AR binding sites was observed after a 15 h SR 59119A treatment.
- Neither PDE4 activity nor the β2‐ and β3‐AR mRNA expression levels were affected by salbutamol or SR 59119A treatments.
- Our results indicate that β3‐AR, but not β2‐AR, are resistant to the agonist‐induced desensitisation. In our model, β2‐AR desensitisation is mediated by a decreased number of β2‐AR that was not explained by transcriptional regulation of the receptor.
British Journal of Pharmacology (2004) 141, 831–841. doi:10.1038/sj.bjp.0705616
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