TRANSCRIPTIONAL MECHANISMS INVOLVED IN THE RELAXANT EFFECT OF ZERANOLON ISOLATED RAT UTERUS

1. The effect of zeranol (3-100 mu M) on rat uterus contractions induc ed by KCl (60 mM) and CaCl2 (30 mu M-10 mM) has been assayed. 2. Zeran ol relaxed the tonic contraction induced by KCl in a concentration-dep endent manner (IC50 15.62+/-2.66 mu M), CaCl2 (0.1-10 mM) did not coun teract the relaxing effect of zeranol. 3. CaCl2 (30 mu M-10 mM) produc ed a concentration-dependent contraction of rat uterus in medium lacki ng calcium plus KCl (60 mM) (EC(50) 0.34+/-0.03 mM). Zeranol (8 mu M) displaced the CaCl2 concentration-response curve to the right and incr eased the EC(50) to 1.27+/-0.57 mM (P<0.05) without modifying the E(ma x). 4. The antiestrogen tamoxifen (1 mu M) and the inhibitor of cAMP-d ependent protein kinase TPCK (3 mu M) did not modify the effect of zer anol. However, the inhibitors of transcription (actinomycin D, 4 mu M) , protein synthesis (cycloheximide, 100 mu M), and ornithine-decarboxi lase (alpha-difluoromethyl ornithine, 10 mM)) antagonized the effect o f zeranol, increasing the IC50 to 50.2+/-6.2 mu M, 122+/-6.9 mu M, and 23.51+/-1.14 mu M, respectively. 5. Our results suggest that the rela xing effect of zeranol on rat uterus smooth muscle is produced by mech anisms unrelated to cAMP and estrogen receptors, but involves transcri ptional effects and polyamine synthesis. (C) 1997 Elsevier Science Inc .