Self-Limitation of Intravenous Tocolysis with β₂-Adrenergic Agonists Is Mediated through Receptor G Protein Uncoupling

Abstract

Tocolysis with a beta-adrenergic receptor agonist is the most common approach to premature labor management after the 25th wk of pregnancy. However, prolonged treatment is associated with a marked loss of efficacy. The biochemical mechanisms involved remain unclear. This study was undertaken to investigate the effect of fenoterol on beta-adrenergic receptor signal transduction in human myometrium. Myometrial biopsy specimens were obtained from 40 women at cesarean section between the 25th and 34th wk of pregnancy. Nineteen patients had received no tocolysis (controls, group I) and 21 had been treated with fenoterol (<48 h in 10, group II; > or = 48 h in 11, group III). As methods we used membrane preparation, adenylyl cyclase assay and cAMP RIA. Adenylyl cyclase activity was determined by the measurement of cAMP levels to evaluate signal transduction after stimulation of beta-adrenergic receptors with isoproterenol, G protein with GTP, and adenylyl cyclase with forskolin. The functional activity of GTP-binding regulatory proteins (G(s)) and adenylyl cyclase was not altered by fenoterol treatment. In the control group, the increase in adenylyl cyclase activity in response to GTP plus isoproterenol was greater than in response to GTP alone. The increase was reduced by 50% in group II and was insignificant in group III. There was no correlation between gestational age and basal adenylyl cyclase activity. Intravenous tocolysis with the beta2-adrenergic receptor agonist fenoterol leads to complete desensitization of the beta-adrenergic receptor system. In addition to the known reduction in receptor number (down-regulation) as underlying mechanism, uncoupling of the receptor from the stimulatory G protein G(s) was identified.

Prenatal exposure to β2-adrenergic receptor agonists and risk of autism spectrum disorders

“…There already is a documented lack of evidence for safety and efficacy of maintenance tocolysis (Larsen et al 1986; The Canadian Preterm Labor Investigators Group 1992; Higby et al 1993; Hudgens and Conradi 1993). Terbutaline’s ability to arrest uterine contractions wanes within 48 h because the beta-2 receptors in the myometrium downregulate and desensitize in response to continuous stimulation (Frambach et al 2005). In addition, other factors that govern uterine contractions are likely to provide a continuing stimulus that is not overcome by B2AR agonists.…”

Effects of β2-Adrenergic Receptor Gene Polymorphisms on Ritodrine Therapy in Pregnant Women with Preterm Labor: Prospective Follow-Up Study

“…This is because clinical outcomes are affected by other factors as well as genetic predisposition. Especially, the long-term efficacy and therapeutic usefulness of β2-agonist drugs have been questioned in many studies, and the limitation of the therapeutic value of β2-agonist drugs was attributable to the desensitization of β-adrenergic receptors in the myometrium by agonist-stimulation [29,30]. In the animal study with preterm labor, ritodrine initially reduced labor contractions but the effects decreased within 16 h [31].…”

“…In the animal study with preterm labor, ritodrine initially reduced labor contractions but the effects decreased within 16 h [31]. The reduced effects were explained by a reduced cAMP response to β2-agonist drugs and by decreased number of β-adrenergic receptors [29,30]. Furthermore, studies showed that neither the Arg16Gly nor the Gln27Glu polymorphism affected the extent of agonist-induced desensitization, but the Glu27 homozygotes exhibited a slower desensitization compared to the other genotypes [32,33].…”

Differential impact of acute and prolonged cAMP agonist exposure on protein kinase A activation and human myometrium contractile activity

“…) and/or G protein uncoupling (Frambach et al . ). However, interest persists in the use of drugs that increase cAMP to inhibit myometrial contractions (Mehats et al .…”