The influence of oestrogen and progesterone on the actions of two calcium entry blockers in the rat uterus

Abstract

The potency and maximum effect of the calcium entry blocker nifedipine as an inhibitor of uterine contractions in vivo are increased in rats in late pregnant compared with non-pregnant rats. The influence of ovarian steroids produced during pregnancy (oestrogen and progesterone) on the potency and maximum effect of two calcium entry blockers (nifedipine and diltiazem) against uterine contractions during i.v. infusion was therefore investigated in anaesthetized non-pregnant rats. The influence of pregnancy on the relationship between serum concentrations of diltiazem during i.v. infusion and uterine and cardiovascular effects was also investigated. A twofold increase in the potency of nifedipine as an inhibitor of uterine contractions was observed in rats treated with oestrogen or oestrogen plus progesterone compared with rats treated with corn oil. There was no change in potency in rats receiving progesterone alone. Maximum inhibition of uterine contractions by nifedipine was significantly increased by all three hormone treatments. A twofold increase in the potency of diltiazem and a significant increase in maximum inhibition of uterine contractions was observed in rats in late pregnancy compared with non-pregnant rats. No increase in potency of diltiazem in reducing blood pressure or heart rate was observed in rats in late pregnancy. No significant difference in potency of diltiazem against uterine contractions was observed in rats treated with oestrogen, progesterone or oestrogen plus progesterone. In order to determine if the hormone-induced changes in the potency of nifedipine against contractions in vivo were due to a direct effect of the ovarian steroids on voltage-operated calcium channels of the uterus or were mediated by extra-uterine mechanisms, the potency of nifedipine as a relaxant of uterine spasms in vitro was investigated. The potency of nifedipine in the isolated uterus as a relaxant of the spasm induced by KC1 did not differ between rats which received oestrogen, progesterone or oestrogen plus progesterone or corn oil. Additionally, the potency of nifedipine to inhibit oxytocin-driven phasic tension development was not affected by treatment with oestradiol. These findings suggest that the increase in potency and maximum effect of nifedipine against uterine contractions observed previously in rats in late pregnancy can be ascribed, in part, to the action of the ovarian steroids (oestrogen and progesterone). The increase in potency of diltiazem observed in rats in late pregnancy, however, is due to factors other than oestrogen and progesterone. The lack of effect of hormonal manipulations on the potency of nifedipine on the isolated uterus suggests that the changes in potency in vivo due to oestrogen and progesterone are mediated by extra-uterine mechanisms. J. Endocr. (1988) 118, 251–258