Effects Of Clozapine On Plasma No,vWF,tPA And PAI-1 In Sprague-daley Rats

Background and PurposeAntipsychotics are the first-line drugs for the treatment of schizophrenia.It has been reported that these drugs,especially clozapine,can increase the risk of venous thrombosis in patients with mental illness.It is speculated that clozapine may increase the risk of venous thromboembolism by damaging vascular endothelial cells.The aim of this study was to investigate the effect of long-term clozapine on vascular endothelial related coagulation function in rats.We noticed that the multi biomarker strategy is a reliable,specific and simple measurement method for the detection of vascular endothelial function through reviewing the relevant literature.It can help us to understand the effect of long-term clozapine administration on blood vessels by measuring endothelial biomarkers involving endothelial protection（such as NO）,coagulation（such as v WF）,fibrinolysis（such as t PA and PAI-1）,and calculating the ratio of PAI-1/t PA,At the same time,several sensitive molecular markers,which reflect the functional status of vascular endothelial cells,were selected as objective indicators to monitor the effect of antipsychotics on vascular endothelial cell function,and to provide reference for evaluating the biological safety of antipsychotics.Materials and MethodsSeven weeks old Male Sprague-Daley rats weighing about 250-280g,were randomly divided into four groups（with 10 or 12 in each group）:（1）Control group;（2）Low-dose clozapine group;（3）Medium dose clozapine group;（4）High-dose clozapine group.Clozapine was dissolved in 5%acetic acid and adjusted to p H 5.0with 0.1 M sodium hydroxide.The low-dose clozapine group was given intraperitoneal injection of 4 mg·kg^-1;the medium dose clozapine group was given intraperitoneal injection of 8 mg·kg^-1;the high-dose clozapine group was given intraperitoneal injection of 16 mg·kg^-1,once a day for 28 consecutive days.After one week of adaptive feeding,the rats were given the drug by intraperitoneal injection once a day for 28 consecutive days.Two hours after the last administration,the blood samples were taken under deep anesthesia and used for detecting the plasma levels of NO,v WF,t PA and PAI-1 by ELISA,the PAI-1/t PA ratio was calculated,and then the animals were killed.ResultsThe plasma levels of NO,v WF,t PA and PAI-1 in the clozapine group were significantly lower than those in the control group.The decreasing levels of v WF,t PA and PAI-1 in rats were correlated with the increasing dosage of clozapine,that show a significant negative correlation and the value for rs being-0.552,-0.727 and-0.607respectively,（p<0.05）.There was a significant positive correlation between the dosage of clozapine and the dosage of clozapine（rs=0.569,p<0.01）.Compared with the control group,the plasma NO level in clozapine group decreased in a dose-dependent manner,although the difference was not significant.Conclusion1.Long term clozapine treatment can reduce the plasma levels of NO,v WF,t PA and PAI-1 in rats,suggesting that clozapine inhibits the secretion of vascular endothelial cells;2.The"low v WF level"is not beneficial for platelet adhesion and aggregation,and it could increasing the risk of bleeding.These all suggest that clozapine can inhibit von Willebrand factor related hemostasis;3.The ratio of PAI-1/t PA in the clozapine group was positively correlated with the dosage of clozapine,suggesting that clozapine could inhibit the fibrinolytic system and promote the hypercoagulability of blood.