Inhibition of the tocolytic activity of atrial natriuretic factor by progesterone and potentiation by progesterone receptor antagonist RU486 in rats.

1. The influence of progesterone on the activity of atrial natriuretic factor (ANF) on rat myometrial motor activity was determined in vitro. 2. ANF inhibited the tension development by myometrium from cycling or oestrogen-treated rats in a dose-dependent manner; maximal inhibition was 100%. 3. Injections of progesterone into rats inhibited the tocolytic activity of ANF in a dose and time-dependent manner. The tocolytic effects of ANF were completely abolished by 3 daily injections of 1 mg kg-1 progesterone. 4. Pregnancy-related increase in plasma progesterone was accompanied by a corresponding decrease in the tocolytic effects of ANF; myometria from gestational day 10 to 21 were completely refractory and those from earlier gestational age and immediate postpartum were responsive to ANF to varying degrees. 5. Treatment of pregnant rats with the progesterone antagonist, RU486, caused abortions and vaginal bleeding, decreased plasma progesterone concentrations and restored the tocolytic activity of ANF. Tocolytic activity of ANF on virgin rat myometria was potentiated by RU486. 6. Progesterone also inhibited the effects of ANF on myometria from ovariectomized rats. 7. Tocolytic activity of isoprenaline was not modified by progesterone, pregnancy, RU486 or ovariectomy. 8. It is concluded that progesterone antagonizes myometrial effects of ANF by an oestrogen-independent mechanism and the pregnancy-induced refractoriness to the tocolytic effects of ANF is caused by progesterone.