Effects of Non-Selective and Selective Beta-Adrenergic Agonists on Spontaneous Contractions and Cyclic AMP Levels in Myometrial Strips from Pregnant Women

Abstract

Isoprenaline and terbutaline relaxed myometrial strips from pregnant women and increased their content of cAMP. The highest measured cAMP concentration, about twice the control level, was determined after a 3-min incubation. Subsequently, the cAMP level declined and approached the basal level after about 60 min. The spontaneous contractions of the myometrial strips were abolished for about 20 min, but reappeared gradually after that time, although the Β-agonists were present in the incubation medium all the time. The decrease of the Β-adrenoceptor responses was not due to an inactivation of the drug tested, or dependent on any diffusible inhibitor substance, since the incubation medium containing the Β-agonist from the 60-min incubation elicited a normal response when added to a fresh myometrial preparation. We suggest that in vitro incubation with high concentrations of Β-agonists induces a desensitization of the Β-receptor of human myometrium.

In Vitro and in Vivo Pharmacological Characterization of Ethyl-4-{trans-4-[((2 S)-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 absence of tolerance gives the drug a clear advantage over the currently used ␤ 2 -mimetics in the perspective of premature labor treatment. Treatment of pregnant women (Berg et al, 1985;Engelhardt et al, 1997) or in vitro treatment of myometrial tissue (Andersson et al, 1980) with a ␤ 2 -adrenoceptor agonist has been widely reported to be associated with a loss in agonist efficacy. This was recently confirmed by a meta-analysis that concluded that available evidence does not support the use of oral ␤-mimetics for maintenance therapy after threatened preterm labor (Dodd et al, 2006).…”

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

“…Our results are in general agreement with the numerous literature on myometrial b 2 -AR desensitisation. For example, it was shown that treatment of pregnant women (Berg et al, 1985;Engelhardt et al, 1997), or in vitro treatment of human myometrial tissue (Andersson et al, 1980) with a b 2 -AR agonist was associated with a loss in efficacy of the b 2 -AR agonist, due to a reduction of the number of b 2 -AR binding sites.…”

“…Human myometrial b-adrenoceptors desensitisation Biochemical study cAMP assay After the 5 or 15 h pretreatment, myometrial strips were equilibrated in Krebs solution (composition as above) continuously gassed with a mixture of 95% oxygen and 5% carbon dioxide at 371C (pH 7.4) for 50 min, and then exposed to the agonists (SR 59119A or salbutamol, each at 10 mM) for 5 min (Andersson et al, 1980). During this 5-min time period, 0.5 mM 3-isobutyl-1-methylxanthine (IBMX), a nonselective inhibitor of cAMP-PDE activity, was added in order to prevent cAMP degradation (Fonteh et al, 1993;Bardou et al, 2000;Boulven et al, 2001).…”

Alpha-drenergic Receptors in Human Myometrium: Changes during Pregnancy

“…Among naturally occurring excitatory re ceptors in the pregnant myometrium, dp and d2-receptors [5], as well as oxytocin and vasopressin receptors [6][7][8], are probably of importance for contraction, whereas myométrial relaxation is mediated by (T-receptors lo cated on the smooth muscle cell membrane [9][10][11], P-Adrenergic receptors have been thoroughly studied, yielding clinically applicable, albeit divergent results in the treatment of preterm labor with so-called P-mimetics [12,13]. d-Adrenergic receptors, on the other hand, have not been as completely studied, and their importance in the regulation of labor is unclear [5], As a step to improved understanding of the myomé trial receptor population, we have studied human myo métrial biopsies from different gestational lengths with regards to the number and kinetics of d r and ob-receptors.…”