Antagonists of embryo-derived platelet-activating factor prevent implantation of mouse embryos

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Abstract
Inhibitors of platelet activation, alprazolam, iloprost and SRI 63-441, were used to demonstrate the necessity of embryo-derived platelet-activating factor (PAF) activity for the establishment of pregnancy in mice. In a splenectomized mouse bioassay 6 .mu.g alprazolam inhibited, for 3 hr, the thrombocytopenia induced by 0.1 .mu.g PAF; 4 .mu.g iloprost and 0.5 .mu.g SRI 63-441 were effective for 6 and 12 h respectively. The administration of 2 .mu.g iloprost/30 g body weight on Days 1 and 4 of pregnancy and twice daily on Days 2 and 3 caused a 50% reduction (P < 0.0005) in the number of implantation sites in the uterus at Day 8 of pregnancy, without affecting (P > 0.05) the number of corpora lutea. A similar reduction in the number of implantation sites was achieved with 20 .mu.g SRI 63-441/30 g body weight/day. The reduction in implantation rate was evident on Day 5 of pregnancy by visualizing the implantation sites with pontamine sky blue. SRI 63-441 had no effect on peripheral blood progesterone concentrations from Day 1 to Day 9 of pregnancy, and did not appear to inhibit implantation by blocking the preimplantation surge of estradiol. The number and morphology of blastocyts flushed from the uterus of Day 4 inhibitor-treated mice was not different (P > 0.05) from the controls. The cleavage rate and morphology of embryos cultured from the 2-cell to blastocyst stage in media containing SRI 63-441 or iloprost (10 .mu./ml) were normal, precluding a gross toxic effect. Simultaneous administration of 1 .mu.g PAF-acether to treated animals re-established pregnancy rates to levels not significantly different (P > 0.05) from the controls.