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

Abstract

1. 1. The effects of several gestagens (pregnenolone [1 to 30 μm], 20α-hydroxypregnenolone [1 to 30 μM]), and 20β-hydroxypregnenolone [1 to 30 μm]) on rat uterine contraction induced by KC1 (60 mM) and CaCl 2 (30 μM to 6 mM) have been assayed. 2. 2. The three drugs relaxed the tonic contraction induced by KCI in a concentration-dependent way. The respective EC 50 values were: 27.6±1.58 μM (pregnenolone), 4.1±0.12 μM (20α-hydroxypregnenolone), and 11.2±1.04 μM (20β-hydroxypregnenolone). CaCl 2 (1 to 10 mM) totally counteracted the relaxing effect of pregnenolone but only partially compared to that of 20α- or 20β-hydroxy-pregnenolone. 3. 3. CaC1 2 (30 μM to 6 mM) produced concentration-dependent contraction of rat uterus in medium lacking calcium plus 30, 60, or 90 mM of KC1. The EC 50 values of CaCl 2 were: 0.38±0.072, 0.183±0.015, and 0.183±0.015 μM in a medium with 30, 60, or 90 mM of KCI, respectively. 4. 4. Pregnenolone (10 μM) did not significantly modify the EC 50 of CaC1 2 in a medium with 30, 60, or 90 mM of KCI. However, 20β-hydroxypregnenolone (10 μM) antagonized, in a noncompetitive manner, the concentration-response curve to CaC1 2. 5. 5. 20α-Hydroxypregnenolone (4 μM) antagonized the concentration-response curve to CaCl 2 in a competitive manner. This antagonism was directly related to the concentration of KCI in the medium. 6. 6. Our results suggest a different calcium antagonist effect of the three gestagens assayed.