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Biology of Reproduction 59, 45-52 (1998)
©Copyright 1998 Society for the Study of Reproduction, Inc.

Molecular Mechanisms of Adenylyl Cyclase Desensitization in Pregnant Rat Myometrium following In Vivo Administration of the ß-Adrenergic Agonist, Isoproterenol

Jean-Luis Lécrivaina, Joëlle Cohen-Tannoudji1,a, Marie-Thérèse Robina, Noëlline Coudouela, Chantal Legranda, , and Jean-Paul Maltiera

a Laboratoire de Physiologie de la Reproduction, CNRS URA 1449, Université P.M. Curie, 75252 Paris Cedex 05, France

ß-Adrenergic agonists are widely used for preterm labor treatment, but their effectiveness may be limited by desensitization. We thus investigated the effects of a ß-agonist, isoproterenol, on the myometrial ß-adrenergic receptor (ß-AR)/adenylyl cyclase pathway after administration in vivo to late-pregnant rats (8 mg/kg, twice-daily injections). One hour after the first injection, isoproterenol-stimulated adenylyl cyclase activity was reduced by 37%. This was associated with a rapid and transient uncoupling of the ß2-ARs (53% reduction of high-affinity receptors). After prolonged isoproterenol treatment (76 h), adenylyl cyclase activity was desensitized not only to isoproterenol but also to guanosine triphosphate and forskolin. Such treatment induced 1) a selective decrease of ß2-ARs as assessed by 125I-cyanopindolol binding, which was reversed by 5'-guanylylimidodiphosphate and thus probably did not involve irreversible loss of receptors, and 2) a rapid alteration of their transcript levels. Prolonged isoproterenol treatment also led to myometrial Gi2{alpha} and Gi3{alpha} increase (44% and 70%) as assessed by Western blotting. Furthermore, pertussis toxin pretreatment of membranes abolished the decrease in isoproterenol-stimulated adenylyl cyclase activity. Thus, we demonstrated that myometrial adenylyl cyclase desensitization after ß-agonist treatment results mainly from ß2-AR uncoupling and increase in Gi activity.

1 Correspondence: Joëlle Cohen-Tannoudji, Laboratoire de Physiologie de la Reproduction, CNRS URA 1449, Université P.M. Curie, 4 Place Jussieu, 75252 Paris Cedex 05, France. FAX: 33-1-44-27-26-50; jtannoud{at}snv.jussieu.fr




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