Activation of the kinin system in the ovary during ovulation: role of endogenous progesterone

Abstract

Background: Previous work by our group and others has implicated a role for kinins in the ovulatory process. The purpose of the present study was to elucidate whether endogenous progesterone, which is an intraovarian regulator of ovulation, might be responsible for induction of the kinin system in the ovary during ovulation. The gonadotropin-primed immature rat was used as the experimental model, and the role of endogenous progesterone was explored using the antiprogestin, RU486.

Results: The results of the study revealed that RU486 treatment, as expected, significantly attenuated ovulation. Activity of the kinin-generating enzyme, kallikrein, was elevated in the ovary in control animals prior to ovulation with peak values observed at 4 h post hCG, only to fall to low levels at 10 h, with a recovery at 20 h post hCG. RU486 treatment had no significant effect on ovarian kallikrein activity as compared to the control group. Total ovarian kininogen levels in control animals increased significantly at 12-14 h after hCG - coinciding with initiation of ovulation. Thereafter, ovarian kininogen levels fell to low levels at 20 h, only to show a rebound from 24-38 h post-hCG. RU486 treatment had no significant effect on the rise of total ovarian kininogen levels from 12-14 h after hCG; however, from 30-40 h post hCG, RU486-treated animals had significantly higher total ovarian kininogen levels versus control animals, suggesting that endogenous progesterone may act to restrain elevations of kininogens in the post-ovulatory ovary. This robust elevation of ovarian kininogen levels by RU486 was found to be primarily due to an increase in T-kininogen, which is a potent cysteine protease inhibitor.

Conclusions: Taken as a whole, these results suggest that endogenous progesterone does not regulate kallikrein activity or kininogens prior to ovulation, but may provide a restraining effect on T-kininogen levels in the post-ovulatory ovary.

Figure 1

Effect of the antiprogestin RU486 upon ovulation rate in PMSG-hCG-primed immature rats. Twenty-three-day-old female rats were primed with 10 IU of PMSG and 48 h later ovulation was induced with hCG (10 IU). Either vehicle or RU486 (10 mg/kg) was administered 30 minutes prior to hCG. n = 6 rats per group. ^** p < 0.03 vs. vehicle.

Figure 2

Effect of RU486 on ovarian steroid levels in the PMSG-hCG-primed immature rat. The model is the same as described in Figure 1. ^* p < 0.05 vs. Vehicle; ^** P < 0.01 vs. Vehicle.

Figure 3

Effect of RU486 on ovarian kallikrein activity in the PMSG-hCG-primed immature rat. The model is the same as described in Figure 1. There is no statistical difference between the groups.

Figure 4

Effect of RU486 on total ovarian kininogen levels in the PMSG-hCG-primed immature rat. The model is the same as described in Figure 1. ^* p < 0.05 vs. Vehicle; ^** p < 0.01 vs. Vehicle.

Figure 5

Species of kininogens in the ovary after RU486 treatment in the PMSG-hCG-primed immature rat. The model is the same as described in Figure 1. ^*p < 0.05 vs. Vehicle; ^** p < 0.01 vs. Vehicle.