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

Abstract

1 In order to compare the b 2 -and b 3 -adrenoceptor (b-AR) desensitisation process in human nearterm myometrium, we examined the influence of a pretreatment of myometrial strips with either a b 2 -or a b 3 -AR agonist (salbutamol or SR 59119A, respectively, both at 10 mM, 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 b-AR desensitisation process, we studied the influence of such treatment on the number of b 2 -and b 3 -AR binding sites, the b 2 -and b 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 Àlog EC 20 values (6.3170.13 vs 5.5870.24, for control and 15 h salbutamol pretreatment, respectively, Po0.05). 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 (0.6070.26 vs 1.5470.24 pmol mg À1 protein, Po0.05), 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 b 2 -but not the b 3 -AR binding site density, whereas no decrease in the number of b 2 -and b 3 -AR binding sites was observed after a 15 h SR 59119A treatment. 6 Neither PDE4 activity nor the b 2 -and b 3 -AR mRNA expression levels were affected by salbutamol or SR 59119A treatments. 7 Our results indicate that b 3 -AR, but not b 2 -AR, are resistant to the agonist-induced desensitisation. In our model, b 2 -AR desensitisation is mediated by a decreased number of b 2 -AR that was not explained by transcriptional regulation of the receptor.

In Vitro and in Vivo Pharmacological Characterization of Ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino]-phenoxy}propyl) Amino]cyclohexyl}benzoate Hydrochloride (SAR150640), a New Potent and Selective Human β3-Adrenoceptor Agonist for the Treatment of Preterm Labor

“…This is apparently due to the lack of recognition sites in the C-terminal tail of the ␤ 3 -adrenoceptor for the cAMP-dependent protein kinase and for the ␤-adrenoceptor kinase implicated in the desensitization of the ␤ 2 -subtype (Strosberg, 1993). We recently confirmed the resistance of the ␤ 3 -adrenoceptor to agonist-induced desensitization in near-term myometrium, whereas ␤ 2 -adrenoceptor undergoes functional desensitization after long-term exposure to salbutamol (Rouget et al, 2004). In the present study, long preincubation with SAR150640 or salbutamol did not modify the ability of SAR150640 to inhibit spontaneous myometrial contractions, indicating the absence of desensitization and cross-desensitization of the ␤ 3 -adrenoceptor.…”

“…The ␤ 3 -adrenoceptor agonist SR59119A was more efficient than salbutamol in vitro in inhibiting human nearterm myometrial spontaneous contractions (Bardou et al, 2000). In addition, the myometrial ␤ 3 -adrenoceptor seems to be resistant to agonist-induced desensitization (Rouget et al, 2004). By contrast, ␤ 2 -adrenoceptor expression is either decreased (Breuiller et al, 1987;Chanrachakul et al, 2003) or unchanged (Gsell et al, 2000) at the end of pregnancy, and there is a loss of response to ␤ 2 -mimetics after chronic exposure to these drugs (Berg et al, 1983).…”

“…These findings attest the drug potential therapeutic application for the treatment of preterm labor. In previous studies, we suggested the potential therapeutic interest of ␤ 3 -adrenoceptor agonists for the treatment of preterm labor (Bardou et al, 2000;Rouget et al, 2004). The human myometrium expresses more ␤ 3 -than ␤ 2 -adrenoceptor, particularly at the end of pregnancy (Rouget et al, 2005).…”

Upregulation of β₃-Adrenergic Receptor mRNA in Human Colon Cancer: A Preliminary Study

“…Thus, for example, in human myometrium, β 2 -AR undergoes functional desensitization after long-term exposure to salbutamol, a β 2 -AR agonist, which is associated with a significant reduction in the number of β 2 -AR binding sites. In contrast, sustained stimulation of the β 3 -AR did not modify its subsequent functional effects, and its binding sites also remained unchanged after such a treatment [17]. Thus, these data suggest that following prolonged activation by the sympathetic nervous system, the β 3 -AR response may be preserved, while the β 1 - and β 2 -AR responses are diminished.…”

Antiarrhythmic effects of beta3-adrenergic receptor stimulation in a canine model of ventricular tachycardia

“…These observations may partially explain the interesting ability of beta3-AR signaling to maintain or even increase its activity following chronic exposure to receptor stimulation. 24,25 Finally, we harvested the tissues roughly one month after the end of beta-3 stimulation. It is possible that there is a rebound increase of beta-3 AR expression due to the withdrawal of the beta-3 stimulation.…”