Study On Relationship Between Renin-Angiotensin System And Fibrinolysis In Spontaneously Hypertensive Rat

Background and objectiveAccumulated clinical data suggest that hypertension is associated with impaired fibrinolysis, epidemiological study has shown that systolic pressure and diastolic pressure are positively related to levels of antigen of both plasminogen activator inhibitor and tissue plasminogen activator. Impaired fibrinolysis may increase the risk of cerebral and coronary thrombotic events in hypertension, but the pathogenesis of decreased fibrinolytic function in hypertension remains to be clarified. Recent studies indicate that the renin-angiotensin system plays an important role in the regulation of vascular fibrinolytic balance and angiotensin II may stimulate the production of PAI-1 in vivo and in vitro. The spontaneously hypertensive rat is a genetic model of hypertension, however, the fibrinolytic activity of SHR in vivo has not been documented. In this study the fibrinolytic function in SHR was evaluated and the effects of captopril and losartan on plasma and local tissue fibrinolytic factors and TGF- 3 j mRNA expressions were observed. The purpose of the study is to investigate the mechanism of reduced fibrinolytic function in hypertension and to establish the relative role of RAS in fibrinolytic dysfunction.Methods12-week-old SHRs were randomly divided into 3 groups, the captopril group(10 rats) received captopril treatment for 4 weeks(100mg/kg/d), losartangroup(10 rats) received losartan treatment(20mg/kg/d), the SHR control group(10 rats) received distilled water. Age matched 10 Wistar rats were used as control group. Blood pressure were measured before and after 4 weeks of treatment, blood sample were taken from the abdominal aorta. The left ventricle, thoracic aorta, liver, kidney and abdominal subcutaneous adipose tissue were rapidly removed and then frozen in liquid nitrogen and stored at -80癈. Plasma activity levels of tissue plasminogen activator and its inhibitor-1 were determined by spectrophotometric assay. A segment of thoracic aorta proximal to the heart was used for immunohistochemical evaluation to detect PAI-1. Total RNA was extracted from these tissue specimens and mRNA expressions were determined by RT-PCR.Results1. Blood pressureBefore treatment mean blood pressure of SHRs and Wistar control rats were 198+4.9 and 127.9+3.8 mmHg, respectively(P<0.0l). Compared with SHR control group, treatmemt of SHRs with captopril and losartan reduced mean blood pressure to 139.6+4.9 mmHg and 141.5+4.8 mmHg, respectively(both P<0.01). After treatment the mean blood presure of SHRs were still higher than that of Wistar control rats(P<0.01).2. Effect of treatment on plasma fibrinolytic activityThere were no significant differences between SHRs and Wistar rats in plasma PAI-1 and t-PA activity. Treatmemt with captopril or losartan did not significantly affect fibrinolytic activity either. Although the ratio of PAI-1 to t-PA in SHR control group was higher than that of treated SHR and Wistar control rats, thedifferences were not statistically significant.3. ImmunohistochemistryIn SHR control group PAI-1 intense immunoreactivity was noted in the endothelium and some part of the vascular media. PAI-1 immunoreavtivity was rarely observed in both Wistar group and captopril group. In losartan group, PA1-1 immunoreavtivity was present in some of the rats, but the intense PAI-1 immunostaining was hardly present. Significant differences were found among the four groups (P<0.05).4. Expression of PAI-1 mRNA , t-PA mRNA and TGF- P1 mRNA4.1 AortaPAI-1: The aortic PAI-1 mRNAs in SHRs were elevated by 3.7-fold compared with Wistar(P<0.0l). Treatment of SHRs with captopil reduced aortic PAI-1 mRNAs by 88%(P<0.01). Treatment with losartan reduced PAI-1 mRNAs expression by 66%(P<0.05).TGF-3^ The aortic TOF-f^ mRNAs expression from SHRs was 5.5 fold higher than that in the Wistar group(P<0. 01). Treatment with captopril reduced aortic TGF- 3 [ mRNAs by 63%(P<0.01). Treatment with losartan did not significantly affect aortic TGF-3} mRNAs levels. PAI-1 mR...