Protective Effects Of Xin-Ji-Er-Kang On Anticardiovascular Remodeling In L-NAME Induced Hypertensive Mice And Its Potential Mechanisms

Objective: To investigate the effects of Xin-Ji-Er-Kang(XJEK)on L-NAME induced hypertension and cardiovascular remodeling in mice and explore the possible mechanism and compare the pharmacological differences in each dose group of XJEK.Methods: A total of 60 Kunming mice were randomly divided into six groups,control group,model group,XJEK low dose group,middle dose group,high dose group and Irbesartan group.Administration of L-NAME(2mg/ml approximately 160 to 180mg/kg/day in drinking water for 8 weeks to induce hypertensive model.While the control group received food and water ad libitum for 8 weeks,the model group received L-NAME for 8 weeks and the XJEK group and Irbesartan group accepted daily intragastric administration of XJEK at a dose of 3.75,7.5,15 g/kg,40 mg/kg since fifth week for 4 weeks when a weekly measurement of the systolic blood pressure(SBP)was performed.Hemodynamic parameters were examined by right carotid artery intubation at the end of 8th week by Transonic Scisense Catheter(U.S.A).After the blood samples were collected,the hearts and thoracic aorta were harvested for further analysis.Cardiac index was calculated via heart weight by body weight(HW/BW).The pathological changes of cardiac and thoracic aorta specimens were observed by Van Gieson(VG)staining and hematoxylin and eosin(HE)for the to observation of the differences in morphology and fibrosis.Colorimetric analysis was used to assay plasma nitric oxide(NO),and thiobarbituric acid method(TBA)and nitrate reductase were used to test the content of malondialdehyde(MDA)and the activity of superoxide dismutase(SOD),respectively.Western blot(WB)and immunohistochemical(IHC)method were applied to detect the levels of protein e NOS in myocardial tissues.Results: Compared with control group,the SBP,HW/BW and hemodynamic parameters of XJEK group decreased significantly(P<0.01,P<0.05).Pathological parameters demonstrated that collagen volume fraction(CVF),myocardial cross-sectional area(CSA),perivascular collagen area(PVCA)and the media thickness(MT)were markedly reduced(P<0.01),which indicated that XJEK could inhibit myocardial fibrosis and ameliorate the remodeling of thoracic aorta.Compared with control group,plasma NO and SOD content were decresaed in model group(P<0.01),and MDA levels were significantly increased in the model group(P<0.01).Compared with model group,the administration of XJEK as well as the positive drug Irbesartan markedly blunted the decrease of plasma NO content and SOD activities(P<0.05),and significantly reduced MDA content(P<0.01,P<0.05),Endothelial nitric oxide synthase protein expression in hearts are significantly improved(P<0.05).Conclusions: XJEK exerts protective effects on L-NAME induced hypertensive mice,and the pharmacological mechanism underlying may be attributed to the improvement of endothelial cell dysfunction,the decrease of ADMA content and the attenuation of oxidative stress,at least in part.