Inhibition of ovulation in the rat by a leukotriene B4 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.

Inhibition of ovulation by a lipoxygenase inhibitor involves reduced cyclooxygenase-2 expression and prostaglandin E2 production in gonadotropin-primed immature rats

“…The induced LOX may be involved in follicular microcirculation and hemodynamics such as chemotaxis, vasodilation, and extravasation. To date, only leukotriene B 4 is shown to be a putative effecter of the LOX pathway eicosanoid because anti-ovulatory effect of NDGA could be reversed by this eicosanoid (Yoshimura et al 1991, Mikuni et al 1998b and was mimicked by its receptor antagonist (Matousek et al 2001). Many important issues, however, remain to be answered such as the identification of the effecter metabolite(s), the spatial and temporal pattern of their synthesis, and action mechanism for the proper induction of PTGS2 protein and other possible activities including tissue degradation/remodeling processes.…”

Membrane Type 1-Matrix Metalloproteinase (MMP)-Associated MMP-2 Activation Increases in the Rat Ovary in Response to an Ovulatory Dose of Human Chorionic Gonadotropin1

“…There is experimental evidence of an increase in mRNA for gelatinases (MMP-2 and MMP-9) and pro-MMP-2 activity following eCG injection to immature rats or administration of hCG to eCG-primed rats [7][8][9]. The importance of MMP-2 and its activation in the ovulatory process is forthcoming from studies in which injection of bioactivity-neutralizing MMP-2 antibody into preovulatory follicles blocked ovulation in ewes [10] and administration of the leukotriene B 4 -receptor antagonist, ZK158252, to rat ovaries inhibits hCG-induced ovulation and MMP-2 activation [11]. However, nothing is known about the regulatory mechanisms by which progelatinases are activated in the ovary during these critical periods.…”

The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study

“…However, it is still unclear which pathway is responsible for these outcomes. It is only known that leukotriene B4 receptor antagonist can cause inhibition of the ovulation in rats [13], that the administration of leukotriene D4 antagonists' results in lack of progression to the luteal phase of the estrous cycle [14] and that corpus luteum produced leukotriene B4 inversely correlated with the secretion rates of progesterone [7]. Furthermore, GnRH antagonist may act on various pathways by inhibiting MAPK [15] or by inducing apoptosis [16] and nitric oxide synthesis [17], explaining potential effects on OHSS.…”