Effects of Xin-Ji-Er-Kang formula on 2K1C-induced hypertension and cardiovascular remodeling in rats

Abstract

Ethnopharmacological relevanceXin-Ji-Er-Kang (XJEK), a Chinese herbal formula, is effective against hypertension induced coronary heart disease, viral myocarditis and toxic myocarditis. In this study, the effect of XJEK on cardiovascular system was investigated. To test the hypothesis that Xin-Ji-Er-Kang (XJEK) has an anti-hypertensive effect mediated through attenuation of cardiac remodeling, and amelioration of vascular endothelial dysfunction and oxidative stress. Materials and methodsHypertension was induced in Wistar rats by 2 kidney 1 clip (2K1C) treatment. The hypertensive rats were then randomly assigned into four groups and treated as follows: group 1 (Sham-operated [Sh-Op] group received only drinking water), group 2 (induced hypertensive model+no treatment), and group 3 (induced hypertensive+a single daily oral dose of 24gkg−1 XJEK treatment) and group 4 (induced hypertensive+a single oral dose of 15mgkg−1 Fosinopril treatment). The rats in all the defined groups were respectively treated for a period of 4 weeks. Cardiovascular parameter such as systolic blood pressure (SBP) was measured weekly by using tail-cuff apparatus; left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and the rate of the rise in left ventricular pressure (±dp/dt max) were measured by using a PowerLab 8/30 apparatus (AD Instruments, Australia) at the end of the 8th week; heart weight/body weight (HW/BW) was determined as an index of myocardial hypertrophy (MH). Hematoxylin and eosin (H&E) and Van Gieson (VG) stain were used to assess the cardio-histological changes. Colorimetric analysis was used to assay serum superoxide dismutase (SOD) activity, malondialdehyde (MDA), nitric oxide (NO), and hydroxyproline (Hyp) contents in cardiac tissue. Angiotensin II (Ang II) content in serum was assessed by radioimmunoassay; tetrahydrobiopterin (BH4) content in cardiac tissue, BNP and endothelial NOS (eNOS) in serum were determined by using ELISA, and the protein expressions of c-Jun NH2-terminal kinase (JNK), P-JNK, p38, P-p38, and NADPH oxidases-2 (Nox-2) were measured by western blot. ResultsXJEK therapy could impair the heart systolic and diastolic function, potently improve the heart weight index, inhibit the elevation of HW/BW ratio, and markedly ameliorate hemodynamic indices and vascular remodeling index. It has blunted the decrease of SOD, NO and the increase in MDA and Ang II serum contents, myocardial cross-section area (CSA), collagen volume fraction (CVF) and perivascular circumferential collagen area (PVCA) compared to the hypertensive model group. It also reduced the serum content of Hyp while increased BH4 levels in cardiac tissue. In addition, the expressions of Nox-2, P-JNK and P-p38MAPK were all suppressed compared to the hypertensive model group. Moreover, treatment with XJEK improved endothelial dysfunction (ED) manifested by promoting eNOS activities and enhancing the NO activity in serum. ConclusionThe results of the present study show that XJEK attenuates 2K1C-induced hypertension in rats, which confirms our hypothesis that XJEK has an anti-hypertensive and cardiovascular remodeling effect via attenuation of cardiac remodeling and improvement of endothelial dysfunction and oxidative stress.