The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibits ovulation and reduces leukotriene and prostaglandin levels in the rat ovary.
Eicosanoids, the active metabolites of arachidonic acid, are grouped into cyclooxygenase products (prostaglandins [PGs] and thromboxanes) and lipoxygenase products (leukotrienes [LTs] and lipoxins). Numerous studies suggest a role for the lipoxygenase system in ovulation. The aim of this study was to further characterize the effects of lipoxygenase inhibition and the interactions of the lipoxygenase and cyclooxygenase systems in the rat ovary during ovulation. The lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), was administered in vivo and in the isolated perfused rat ovary to determine its effect on ovulation rate. The in vivo study confirmed the inhibitory effect of NDGA, and in the perfusion experiments, NDGA caused a dose-dependent reduction in the ovulation rate. To further define the interaction between the lipoxygenase and cyclooxygenase systems, a second set of perfusions was performed with NDGA (10 microM) and the combination of NDGA (10 microM) plus a nonselective cyclooxygenase inhibitor, indomethacin (10 microM). NDGA significantly reduced the number of ovulations compared to that in controls. The ovulation rate for the combination of NDGA+indomethacin was also significantly lower than in controls but not different from that in the NDGA-treated group. Steroidogenesis was decreased only in the NDGA+indomethacin perfusions. Ovarian tissue PGE2 and PGF2alpha levels in the NDGA-treated ovaries were significantly suppressed compared to those in controls. Almost a complete block of PGE2 and PGF2alpha was seen in the NDGA+indomethacin group. LTB4 levels in the 10-h-perfused ovarian tissues were significantly decreased by NDGA compared to those in control tissues. Furthermore, LTB4 (3 microg added twice) completely reversed the inhibitory effect of 0.1 microM NDGA on ovulation rate and partially reversed the effect of 10 microM NDGA in the perfusion model. These results demonstrate that the products of the lipoxygenase pathway, especially LTB4, are important in the process of ovulation in this cyclically ovulating species. The interconnected lipoxygenase and cyclooxygenase pathways may optimize ovulation and facilitate steroidogenesis.
Mikuni
M
M
Department of Obstetrics and Gynecology, Göteborg University, Sweden. nobhoshi@med.hokudai.ac.jp
Yoshida
M
M
Hellberg
P
P
Peterson
C A
CA
Edwin
S S
SS
Brännström
M
M
Peterson
C M
CM
D000818:Animals; D003864:Depression, Chemical; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009637:Masoprocol / Q000494:pharmacology*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism*; D010060:Ovulation / Q000187:drug effects*; D011374:Progesterone / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D011374:Progesterone; D004958:Estradiol; D009637:Masoprocol