Inhibition of ovulation in the rat by a leukotriene B(4) receptor antagonist.

Abstract

The involvement of leukotriene (LT) B(4) in the ovulatory process of the rat was investigated by the use of a LTB(4)-receptor antagonist (ZK158252 = L-ANT) administered either intrabursally in vivo or to the in-vitro perfused ovary. The in-vivo experiments revealed inhibition of human chorionic gonadotrophin (HCG)-induced ovulation by 500 micromol/l L-ANT (median 5.5, 25-75% range 1.0-6.0) compared with controls (median 9.0, range 6.25-13.5). In vitro, ovulation was induced by LH (0.2 microg/ml) + 3-isobutyl-1-methylxanthine (IBMX; 0.2 mmol/l). The ovary was perfused either for 20 h, to study ovulation rate, or for 10 h to examine ovarian concentrations of the ovulatory mediators matrix metalloproteinase (MMP)-2 and MMP-9, plasminogen activator (PA), prostaglandin (PG)E(2) and PGF(2 alpha). Addition of LH+IBMX resulted in a marked stimulation of steroid release and ovulations occurred in all ovaries (median 11.0, range 10.0-14.0). The L-ANT inhibited ovulation in a dose-dependent way (median 10.0, range 8.0-13.0 at 1 micromol/l; median 6.0, range 3.5-10.0 at 10 micromol/l; median 2.0, range 0.75-5.75 at 100 micromol/l). The intra-ovarian activity of PA was increased 1.5-fold by L-ANT (100 micromol/l), but the concentrations of PGE(2) and PGF(2 alpha) remained unaltered. While no changes in MMP-9 were observed, conversion from pro-MMP-2 to active MMP-2 was inhibited by L-ANT. These results suggest that activation of the LTB(4)-receptor within the ovary is involved in the ovulatory process and that the effects of LTB(4)-receptor activation are partly mediated via MMP-2.