Relationship between Oxidative Stress and Essential Hypertension

1159 Hypertens Res Vol.30 (2007) No.12 p.1159-1167 Original Article Relationship between Oxidative Stress and Essential Hypertension Ramón RODRIGO1), Hernán PRAT2), Walter PASSALACQUA3), Julia ARAYA4), Cristián GUICHARD1), and Jean P. BÄCHLER1) This study investigated the association of blood pressure with blood oxidative stress–related parameters in normotensive and hypertensive subjects. A cross-sectional design was applied to 31 hypertensive patients and 35 healthy normotensive subjects. All subjects were men between the ages of 35 and 60 years. Exclusion criteria were obesity, dyslipidemia, diabetes mellitus, smoking and current use of any medication. All patients underwent 24-h ambulatory blood pressure monitoring and sampling of blood and urine. Antioxidant enzymes activity, reduced/oxidized glutathione ratio (GSH/GSSG), and lipid peroxidation (malondialdehyde) were determined in erythrocytes. Parameters measured in the plasma of test subjects were plasma antioxidant status, lipid peroxidation (8-isoprostane), plasma vitamin C and E, and the blood pressure modulators renin, aldosterone, endothelin-1 and homocysteine. Daytime systolic and diastolic blood pressures of hypertensives were negatively correlated with plasma antioxidant capacity (r = – 0.46, p < 0.009 and r = –0.48, p < 0.007), plasma vitamin C levels (r = – 0.53, p < 0.003 and r = – 0.44, p < 0.02), erythrocyte activity of antioxidant enzymes, and erythrocyte GSH/GSSG ratio, with hypertensives showing higher levels of oxidative stress. Blood pressures showed a positive correlation with both plasma and urine 8-isoprostane. Neither plasma vitamin E nor the assessed blood pressure modulator levels showed significant differences between the groups or correlation with blood pressures. These findings demonstrate a strong association between blood pressure and some oxidative stress–related parameters and suggest a possible role of oxidative stress in the pathophysiology of essential hypertension. (Hypertens Res 2007; 30: 1159–1167) Key Words: antioxidants, essential hypertension, 8-isoprostane, oxidative stress, vitamin C Introduction Increased vascular oxidative stress could be involved in the pathogenesis of hypertension (1, 2), a major risk factor for cardiovascular disease mortality. Oxidative stress occurs when there is an imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defense systems so that the latter become overwhelmed (3, 4). In human essential hypertension ROS may increase due to a diminution of the activity of antioxidant enzymes (5). The importance of ROS in vascular function and the development of hypertension has been recently reviewed (6, 7). It is known that superoxide rapidly inactivates endothelium-derived nitric oxide (NO), the most important endogenous vasodilator, thereby promoting vasoconstriction (8, 9). Thus oxidative stress may account for endothelial dysfunction, but it is unknown whether this abnormality is a primary event or a consequence of increased From the 1)Laboratory of Renal Pathophysiology, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, 2) Cardiovascular Center and 3)Nephrology Unit of Department of Medicine, Clinical Hospital, and 4)Department of Nutrition, Faculty of Medicine, University of Chile, Santiago, Chile. This study was supported by grants from FONDECYT (grant number 1040429, Chile Government), Procaps Laboratory (Colombia) and Gynopharm CFR Laboratory (Chile). Address for Reprints: Ramón Rodrigo, Laboratory of Renal Pathophysiology, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Casilla 70058, Santiago 7, Chile. E-mail: Received March 12, 2007; Accepted in revised form July 3, 2007. 1160 Hypertens Res Vol. 30, No. 12 (2007) Table 1. Clinical Characteristics of Essential Hypertensive Patients (n=31) and Healthy Normotensive Subjects (n=35) Characteristic Normotensive subjects Hypertensive patients p value Age (years) Body mass index (kg/m2) Serum glucose (mmol/L) Creatinine (μmol/L) Total cholesterol (mmol/L) HDL-cholesterol (mmol/L) LDL-cholesterol (mmol/L) Serum triglycerides (mmol/L) Daytime SBP (mmHg) Daytime DBP (mmHg) Heart rate (beats/min) 44.4±1.3 25.5±0.4 4.94±0.07 80.4±1.6 4.54±0.16 1.29±0.07 2.69±0.16 1.33±0.08 119.5±0.8 78.2±0.8 71.6±1.3 45.9±1.6 26.2±0.3 5.11±0.10 82.2±2.2 4.86±0.13 1.21±0.04 2.90±0.11 1.53±0.10 137.5±0.2 91.9±1.3 73.5±1.1 0.48 0.17 0.16 0.52 0.13 0.31 0.26 0.10 <0.001* <0.001* 0.28 Values are means±SEM. HDL, high density lipoprotein; LDL, low density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure. *Significant difference by unpaired t-test. Table 2. Plasma Blood Pressure Modulator Levels in the Study Participants Modulator Normotensive subjects (n=35) Hypertensive patients (n=31) p value Renin activity (pmol/L/h) Aldosterone (nmol/L) Endothelin-1 (pmol/L) Homocysteine (μmol/L) Folic acid (nmol/L) Vitamin B12 (pmol/L) 26.07±4.00 0.24±0.02 2.72±0.25 8.85±0.31 43.49±1.49 228.2±9.3 20.86±2.64 0.26±0.02 2.45±0.33 9.91±0.51 46.6±1.27 233.4±7.87 0.29 0.47 0.51 0.07 0.12 0.73 Values are means±SEM. blood pressure (10). In keeping with the above results, acute pressure overload has been reported to induce self-limited superoxide production in the vascular wall (11). Attempts to counteract the hypertensive effect of ROS have led to the use of exogenous administration of antioxidants thought to improve the vascular function and reduce the blood pressure in animal models (12, 13) and in human hypertension (14, 15). Nevertheless, the available data are not conclusive and the relationship between blood pressure and oxidative stress in humans remains to be elucidated. The purpose of the present study was to investigate the association of blood pressure with oxidative stress in volunteer male normotensive and essential hypertensive subjects. Methods Study Design A cross-sectional design was applied to 31 hypertensive patients and 35 healthy normotensive subjects. The study protocol was approved by the Ethics Committee of the University of Chile Clinical Hospital, in accordance with the Helsinki Declaration (Edinburgh revision, 2000). All partici- pants signed a written consent form and no complications were encountered during the study. Patients We recruited untreated essential hypertensive outpatients (stage 1) (16). All subjects were males between the ages of 35 and 60 years. Hypertension was defined as mean daytime blood pressure values ≥ 135 mmHg systolic or ≥ 85 mmHg diastolic, by ambulatory blood pressure monitoring (17). Exclusion criteria were smoking, obesity (body mass index [BMI] > 30 kg/m2), diabetes, hypercholesterolemia, chronic diseases, and current use of any medication, including dietary supplements. Normotensive volunteer subjects participated as controls. The potential participants were subj (...truncated)