Molecular mechanisms of adenylyl cyclase desensitization in pregnant rat myometrium following in vivo administration of the beta-adrenergic agonist, isoproterenol.

Abstract

Beta-adrenergic agonists are widely used for preterm labor treatment, but their effectiveness may be limited by desensitization. We thus investigated the effects of a beta-agonist, isoproterenol, on the myometrial beta-adrenergic receptor (beta-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 beta2-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 beta2-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 Gi2alpha and Gi3alpha 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 beta-agonist treatment results mainly from beta2-AR uncoupling and increase in Gi activity.

• Authors: J L Lécrivain, J Cohen-Tannoudji, M T Robin, N Coudouel, C Legrand, J P Maltier
• Journal: Biology of reproduction (Biol Reprod) Vol. 59 Issue 1 Pg. 45-52 (Jul 1998) ISSN: 0006-3363 [Print] United States
• PMID: 9674992 (Publication Type: Journal Article)

Chemical References

• Adrenergic beta-Agonists
• Adrenergic beta-Antagonists
• RNA, Messenger
• Receptors, Adrenergic, beta
• Colforsin
• Guanylyl Imidodiphosphate
• cyanopindolol
• Guanosine Triphosphate
• Pindolol
• GTP-Binding Proteins
• Adenylyl Cyclases
• Isoproterenol

Topics

• Adenylyl Cyclases (metabolism)
• Adrenergic beta-Agonists (pharmacology)
• Adrenergic beta-Antagonists (metabolism)
• Animals
• Colforsin (pharmacology)
• Drug Tolerance
• Female
• GTP-Binding Proteins (physiology)
• Guanosine Triphosphate (pharmacology)
• Guanylyl Imidodiphosphate (pharmacology)
• Isoproterenol (administration & dosage, pharmacology)
• Myometrium (drug effects, enzymology)
• Pindolol (analogs & derivatives, metabolism)
• Pregnancy
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Receptors, Adrenergic, beta (drug effects, genetics, physiology)