Tocolytic therapy with fenoterol induces selective down-regulation of β-adrenergic receptors in human myometrium

Tocolytic therapy with β-adrenergic receptor agonists is a standard regimen to prevent preterm birth. Agonist exposure of β-adrenergic receptors causes receptor desensitization in other organs, and this may limit the therapeutic value of β-adrenergic receptor agonists. To study the effects of prolonged β-adrenergic agonist treatment in human myometrium, we obtained biopsies during Caesarean section of 14 pregnant patients who had received fenoterol for at least 5 days and 14 untreated pregnant controls. The densities of total β-adrenergic receptors, which are mainly of the β₂- subtype as assessed by [¹²⁵I]iodo-cyanopindolol binding in crude membrane fractions, were more than 50% smaller in women receiving fenoterol, whereas α₂-adrenergic receptor densities were similar. G(a) and G(i) G-protein α- subunit densities were unaltered as assessed by Western blotting and pertussis toxin-catalyzed [³²P]ADP-ribosylation. β-Adrenergic receptor kinase (βARK) activity, as determined using bovine rhodopsin as the substrate, was the same in the two groups. Adenylyl cyclase activities in the presence of guanine nucleotides, NaF, forskolin, or Mn⁺⁺ were also not altered by fenoterol treatment. The messenger RNA (mRNA) concentrations of β₂-adrenergic receptors, βARK-I and glyceraldehyde-3-phosphate dehydrogenase (as a reference), as determined by quantitative PCR, were unaffected by fenoterol treatment. We conclude that tocolysis with fenoterol results in a selective down-regulation of myometrial β-adrenergic receptors, which is not associated with a reduction in the respective mRNA concentrations or alterations of α₂-adrenergic receptors, G(a) and G(i) α- subunits, or βARK activity or mRNA.