| Objective: Cardiovascular remodeling is a hallmark of hypertension-inducedpathophysiology. The aims of the study were to investigate whether grape seedproanthocyanins (GSP) prevent or reverse hypertension and cardiovascular remodelingin deoxycortocorticosterone acetate (DOCA)-salt hypertension rats and to explore itsrelated mechanism(s).Methods:54male Sprague-Dawley (SD) rats were randomly divided into7groupsincluding Sham group (n=7), UnX-Sham group (n=8), DOCA-salt group (n=8),GSP150group (GSP150mg/kg, n=7), GSP240group (GSP240mg/kg, n=8), GSP384group (GSP384mg/kg, n=8) and ALM group (ALM5mg/kg, n=8). All rats wereuninephrectomized (UNX) except Sham group animals. Three days after leftnephrectomy, animals in DOCA-salt group and GSP or ALM treating groups wereadministered with DOCA (120mg/kg s.c.) weekly, and1％NaCl and0.2%KCl wereadded into their drinking water for4weeks continuously to induce DOCA-salthypertension. In addition, GSP150,240,384mg/kg or ALM5mg/kg was dailyadministered to DOCA-salt hypertension animals intragastrically (ig) for4weeksrespectively. Sham group animals were subjected with the same surgical procedurewithout moving the left kidney. Sham and UnX-Sham animals serving as controls wereadministered with distilled water intragastrically without1％NaCl or0.2%KCl intheir drinking water for4weeks. Blood pressures were measured indirectly byALC-NIBP in conscious weekly. BL420S biological function testing system wasemployed to examine the left ventricular function and heart weight/body weight(HW/BW) ratio was calculated after4weeks’ treatments. Endothelium-dependent relaxations due to acetylcholine were observed in isolated rat thoracic aortic ringpreparation. The histological changes of heart and vascular were investigated byhematoxylin and eosin (HE) staining and Van Gieson (VG) staining. Surperoxidedismutase (SOD) activity, malondialdehyde (MDA) and nitrogen monoxide (NO)content in serum were studied by colorimetry. The brain natriuretic paptide (BNP) andendothelin-1(ET-1) content in serum were measured by Enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) respectively. The phosphorylationlevels of JNK1/2and p38MAPK were investigated by Western blot analysis.Results: There were no statistical significant changes when comparing Sham group andUnX-Sham group. Blood pressures of DOCA-salt hypertension animals were increasedto168.53±4.21mmHg (P﹤0.01vs Sham group) and195.35±13.58mmHg (P<0.01vs Sham group) at1and4weeks respectively after uninephrectomization. However, thehigh blood pressure of rats in GSP and ALM treating groups were reduced significantly(P﹤0.01vs DOCA-salt group).Comparing with Sham controls, DOCA-salt rats presented significant reduction inleft ventricular systolic pressure (LVSP) and maximal rate of left ventricularsystolic/diastolic pressure (±dp/dtmax)(P﹤0.01), and significant increase in leftventricular end-diastolic pressure (LVEDP)(P﹤0.01). HW/BW ratio was increasedmarkedly as well (P﹤0.01). The cardiomyocytes cross-section area (CSA), collagenvolume fraction (CVF) and perivascular circumferential collagen area (PVCA) weregradually increased (P﹤0.01) shown by HE and VG staining. Different dosages of GSPand ALM treatments significantly increased LVSP and±dp/dtmax, and progressivelyreduced LVEDP (P﹤0.05vs DOCA-salt group). HW/BW ratio was decreased indose-dependent (P﹤0.05vs DOCA-salt group). And the morphology of cardiachypertrophy was improved as well.SOD activities and NO contents in DOCA-salt hypertension rats were decreased gradually with MDA contents were gradual increased (P﹤0.01vs Sham group). Aorticrings showed strongly weaker endothelium-dependent vasodilator responses toacetylcholine (P﹤0.01vs Sham group). And the total area of arota (TAA), area oflumen (LA), cross-section area (CSA), CSA/TAA, arota radium (AR), media thickness(MT) and MT/LR were increased significantly (P﹤0.05, P﹤0.01vs Sham group).Comparing with DOCA-salt group, treatments of GSP and ALM improved aroticremodeling (P﹤0.01), and endothelium-dependent vasodilator responses toacetylcholine were stronger, SOD activities were also reversed (P﹤0.05, P﹤0.01) andMDA contents were increased (P﹤0.01). NO contents were increased to12.30±1.92,14.92±3.91and13.53±5.11μmol/L in240,384mg/kg of GSP and ALM treatmentsgroups respectively (P﹤0.05, P﹤0.01).The contents of ET-1and BNP in DOCA-salt rats were markedly increased (P﹤0.01vs Sham group), as well as the content of Hyp in cardiac tissue (P<0.01vs Shamgroup). The phosphorylation levels of JNK and p38MAPK in cardiac tissue werestrongly upregulated (P﹤0.05vs Sham group). Otherwise the contents of ET-1andBNP were reduced significantly following GSP384mg/kg treatment (P﹤0.05vsDOCA-salt group), the content of Hyp in cardiac tissue was reduced in dose-dependent,and the expression levels of phosphorylated JNK and p38MAPK were progressivelydecreased (P﹤0.05vs DOCA-salt group).Conclusion: GSP has protective effect against DOCA-salt hypertension, and improvescardiovascular remodeling by inhibiting the ROS-MAPK pathway via restraining therelease of ET-1. |
PDF Full Text Request