Calcium and depolarization-dependent effect of pregnenolone derivatives on uterine smooth muscle.

1. The effects of several gestagens (pregnenolone [1 to 30 microM], 20 alpha-hydroxy-pregnenolone [1 to 30 microM], and 20 beta-hydroxypregnenolone [1 to 30 micro M]) on rat uterine contraction induced by KCl (60 mM) and CaCl2 (30 microM to 6 mM) have been assayed. 2. The three drugs relaxed the tonic contraction induced by KCl in a concentration-dependent way. The respective EC50 values were: 27.6 +/- 1.58 microM (pregnenolone), 4.1 +/- 0.12 microM (20 alpha-hydroxy-pregnenolone), and 11.2 +/- 1.04 microM (20 beta-hydroxypregnenolone). CaCl2 (1 to 10 mM) totally counteracted the relaxing effect of pregnenolone but only partially compared to that of 20 alpha- or 20 beta-hydroxy-pregnenolone. 3. CaCl2 (30 microM to 6 mM) produced concentration-dependent contraction of rat uterus in medium lacking calcium plus 30, 60, or 90 mM of KCl. The EC50 values of CaCl2 were: 0.38 +/- 0.072, 0.183 +/- 0.015, and 0.183 +/- 0.015 mM in a medium with 30, 60, or 90 mM of KCl, respectively. 4. Pregnenolone (10 microM) did not significantly modify the EC50 of CaCl2 in a medium with 30, 60, or 90 mM of KCl. However, 20 beta-hydroxypregnenolone (10 microM) antagonized, in a noncompetitive manner, the concentration-response curve to CaCl2. 5. 20 alpha-Hydroxypregnenolone (4 microM) antagonized the concentration-response curve to CaCl2 in a competitive manner. This antagonism was directly related to the concentration of KCl in the medium. 6. Our results suggest a different calcium antagonist effect of the three gestagens assayed.