title: Transcriptional mechanisms involved in the relaxant effect of zeranol on isolated rat uterus.
abstract: 1. The effect of zeranol (3-100 microM) on rat uterus contractions induced by KCl (60 mM) and CaCl2 (30 microM-10 mM) has been assayed. 2. Zeranol relaxed the tonic contraction induced by KCl in a concentration-dependent manner (IC50 15.62 +/- 2.66 microM). CaCl2 (0.1-10 mM) did not counteract the relaxing effect of zeranol. 3. CaCl2 (30 microM -10 mM) produced a concentration-dependent contraction of rauuterus in medium lacking calcium plus KCl (60 mM) (EC50 0.34 +/- 0.03 mM). Zeranol (8 microM) displaced the CaCl2 concentration-response curve to the right and increased the EC50 to 1.27 +/- 0.57 mM (P < 0.05) without modifying the Emax. 4. The antiestrogen tamoxifen (1 microM) and the inhibitor of cAMP-dependent protein kinase TPCK (3 microM) did not modify the effect of zeranol. However, the inhibitors of transcription (actinomycin D, 4 microM), protein synthesis (cycloheximide, 100 microM), and ornithine-decarboxilase (alpha-difluoromethyl-ornithine, 10 mM)) antagonized the effect of zeranol, increasing the IC50 to 50.2 +/- 6.2 microM, 122 +/- 6.9 microM, and 23.51 +/- 1.14 microM, respectively. 5. Our results suggest that the relaxing effect of zeranol on rat uterus smooth muscle is produced by mechanisms unrelated to cAMP and estrogen receptors, but involves transcriptional effects and polyamine synthesis.
authors.affiliation: Department of Medicine, Pharmacology Laboratory, Faculty of Medicine C. Julian Clavería, Oviedo, Spain.
authors.forename: M P
authors.initials: MP
authors.lastname: Revuelta
authors.forename: B
authors.initials: B
authors.lastname: Cantabrana
authors.forename: A
authors.initials: A
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D065108:Ornithine Decarboxylase Inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects* / Q000502:physiology; D015029:Zeranol / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004968:Estrogens, Non-Steroidal; D065108:Ornithine Decarboxylase Inhibitors; D011500:Protein Synthesis Inhibitors; D013629:Tamoxifen; D003609:Dactinomycin; D015029:Zeranol; D003513:Cycloheximide; D017868:Cyclic AMP-Dependent Protein Kinases; D000518:Eflornithine