[Effects of raloxifene combined with conjugated equine estrogen on prothrombotic state in ovariectomized rats].
OBJECTIVE
To study effects of raloxifene (RLX) with different doses of conjugated equine estrogen(CEE) on prothrombotic profiles in the ovariectomized rats model.


METHODS
Total of 32 healthy female SD rats at age of 9 to 10 months were equally divided into every 8 rats at 4 groups randomly. One week after ovariectomized, they were treated by drugs, including control group with placebo(0.9% Nacl intragastric administration), RLX group with RLX 6 mg/(kg·d), RLX and low CEE group with RLX 6 mg/(kg·d) + CEE 0.07 mg/ (kg·d) and RLX and high CEE group with RLX 6 mg/ (kg·d) + CEE 0.5 mg/ (kg·d) for 10 weeks before death. Thrombin turbidimetry method was used to evaluate the plasma fibrinogen(FIB), transmitting substrate method for antithrombin III(ATIII) activity, double-antibody sandwich ELISA for plasminogen activator inhibitor 1 (PAI-1), D-dimer (D-D) and von Willebrand factor (vWF) and nitrate reductase method for nitric oxide(NO).


RESULTS
(1) Coagulation and anticoagulation indicators: it was observed (1.62 ± 0.22) g/L FIB at control group, (2.02 ± 0.54) g/L at RLX group, (1.97 ± 0.16) g/L at RLX and low CEE group, (2.00 ± 0.18) g/L at RLX and high CEE group. There was a statistically significant difference between control group and any one of treatment groups (P < 0.05) and no statistical significance among those three treatment groups (P > 0.05). No significant change was observed in plasma ATIII activity among groups (P > 0.05). (2) Fibrinolytic and anti-fibrinolytic indicators: it was observed (14.1 ± 2.8) µg/L PAI-1 at control group, (20.0 ± 3.3) µg/L at RLX group, (41.5 ± 5.5) µg/L at RLX and low CEE group, (38.9 ± 6.0) µg/L at RLX and high CEE group. A remarkable increase was observed between control group and any one of treatment groups (P < 0.05) . But there was no significant difference of D-D among groups (P > 0.05) . (3) Endothelial function: it was (43 ± 7) % vWF at control group, (49 ± 5) % at RLX group, (46 ± 6) % at RLX and low CEE group, (36 ± 5) % at RLX and high CEE group. The vWF of RLX and high CEE group was the lowest among all groups (P < 0.05) . There was no difference of NO among groups (P > 0.05).


CONCLUSIONS
In the different links of thrombosis, RLX gives different function and may increase the risk. CEE plays a synergism role in the matter of fibrinolysis and anti-fibrinolysis with RLX, further giving rise to thrombosis effect of RLX. And it also has a protective role in the function of vascular endothelium to some extent. But this only works with high dose.
Department of Obstetrics and Gynecology, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing 100050, China.
Hui
H
Gao
Shui
S
Xi
100730 Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. Email: xuling@pumch.cn.
Ling
L
Xu
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D004195:Disease Models, Animal; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects; D010052:Ovariectomy; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D013927:Thrombosis / Q000209:etiology* / Q000517:prevention & control
D004966:Estrogens, Conjugated (USP); D017395:Plasminogen Activator Inhibitor 1; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D000990:Antithrombin III; D005340:Fibrinogen