PROGESTERONE AND PREGNANOLONE DERIVATIVES RELAXING EFFECT ON SMOOTH-MUSCLE

1. The effect of gestagens, 5 alpha-hydroxyprogesterone (10(-6)-6 x 10(-5) M), 5 beta-hydroxyprogesterone (10(-6)-3 x 10(-5) M), progesterone (6 x 10(-6)-10(-4) M), pregnanolone (10(-6)-10(-5) M), allopregnanolone (10(-6)-10(-4) M) and epipregnanolone (10(-6)-6 x 10(-5) M) on rat uterine contractions induced by KCl (60 mM), has been assayed. 2. All drugs assayed relaxed the tonic-contraction induced by KCl in a concentration-dependent way. The respectives IC50 were 31.3 +/- 4.1 x 10(-6) M (progesterone), 8.9 +/- 0.8 x 10(-6) M (5 alpha-hydroxyprogesterone), 3.8 +/- 0.3 x 10(-6) M (5 beta-hydroxyprogesterone), 3.1 +/- 0.1 x 10(-6) M (pregnanolone), 21.2 +/- 3.1 x 10(-6) M (allopregnanolone) and 6.3 +/- 1.3 x 10(-6) M (epipregnanolone). This relaxing effect was partially or totally counteracted by CaCl2, (1-10 mM). 3. Cycloheximide (10 mu g/ml) significantly shifted to the right the effect of allopregnanolone but not the effect of the other drugs. Actinomycin D (5 mu g/ml) did not modify the effect of allopregnanolone. 4. Our results suggest that the relaxing effect of gestagens in the rat uterus could be related to inhibition on calcium influx and mainly occur through non-genomic mechanisms.