TOCOLYTIC THERAPY WITH FENOTEROL INDUCES SELECTIVE DOWN-REGULATION OFBETA-ADRENERGIC RECEPTORS IN HUMAN MYOMETRIUM

Tocolytic therapy with p-adrenergic receptor agonists is a standard re gimen to prevent preterm birth. Agonist exposure of beta-adrenergic re ceptors causes receptor desensitization in other organs, and this may limit the therapeutic value of beta-adrenergic receptor agonists. To s tudy the effects of prolonged beta-adrenergic agonist treatment in hum an myometrium, we obtained biopsies during Caesarean section of 14 pre gnant patients who had received fenoterol for at least 5 days and 14 u ntreated pregnant controls. The densities of total beta-adrenergic rec eptors, which are mainly of the beta(2)-subtype as assessed by [I-125] iodo-cyanopindolol binding in crude membrane fractions, were more than 50% smaller in women receiving fenoterol, whereas alpha(2) adrenergic receptor densities were similar. G(s) and G(i) G-protein alpha-subuni t densities were unaltered as assessed by Western blotting and pertuss is toxin-catalyzed [P-32]ADP-ribosylation. beta-Adrenergic receptor ki nase (beta ARK) 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) conc entrations of beta(2)-adrenergic receptors, beta ARK-I and glyceraldeh yde-3-phosphate dehydrogenase (as a reference), as determined by quant itative PCR, were unaffected by fenoterol treatment. We conclude that tocolysis with fenoterol results in a selective down-regulation of myo metrial beta-adrenergic receptors, which is not associated with a redu ction in the respective mRNA concentrations or alterations of alpha(2) -adrenergic receptors, G(s) and G(i) alpha-subunits, or beta ARK activ ity or mRNA.