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

1. The effects of several gestagens (pregnenolone [1 to 30 mu M], 20 alpha-hydroxypregnenolone [1 to 30 mu M], and 20 beta-hydroxypregnenolone [1 to 30 mu M]) on rat uterine contraction induced by KCl (60 mM) and CaCl2 (30 mu M to 6 mM) have been assayed. 2. The three drugs relaxed the tonic contraction induced by KCl in a concentration-dependent way. The respective ECS, values were: 27.6+/-1.58 mu M (pregnenolone), 4.1+/-0.12 mu M (20 alpha-hydroxypregnenolone), and 11.2+/-1.04 mu M (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-hydroxypregnenolone. 3. CaCl2 (30 mu M to 6 mM) produced concentration-dependent contraction of rat uterus in medium lacking calcium plus 30, 60, or 90 mM of KCl. The EC(50) 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 mu M) did not significantly modify the EC(50) of CaCl2 in a medium with 30, 60, or 90 mM of KCl. However, 20 beta-hydroxypregnenolone (10 mu M) antagonized, in a noncompetitive manner, the concentration-response curve to CaCl2. 5. 20 alpha-Hydroxypregnenolone (4 mu M) 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.