Lowering of Blood Pressure Leads to Decreased Circulating Interleukin-6 in Hypertensive Subjects

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Journal of Human Hypertension (2005) 19, 457–462 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Lowering of blood pressure leads to decreased circulating interleukin-6 in hypertensive subjects

GVa´zquez-Oliva1, JM Ferna´ndez-Real2, A Zamora1, M Vilaseca1 and L Badimo´n3 1Cardiology Unit, Hospital de Blanes, Corporacio´ de Salut del Maresme i La Selva, Girona, Spain; 2Section of Diabetes, Endocrinology and Nutrition, Hospital Universitari de Girona ‘Dr Josep Trueta’, Girona, Spain; 3Cardiovascular Research Center, ICCC-CSIC, Hospital de Sant Pau, Barcelona, Spain

Interleukin-6 (IL-6), the major proinflammatory cytokine, At baseline, circulating IL-6 levels, but not adhesion has been described to be associated with the hyperten- molecules, were significantly associated with systolic sive and atherosclerotic states. We aimed to explore blood pressure (r ¼ 0.41; P ¼ 0.03) and BMI (r ¼ 0.53; whether the concentration of circulating IL-6 and adhe- P ¼ 0.005). Systolic and diastolic blood pressure de- sion molecules could be modified by decreasing blood creased significantly (Po0.01) in parallel to serum IL-6 pressure in hypertensive subjects. A total of 30 subjects levels (from 3.7270.82 to 3.2370.19 pg/ml, P ¼ 0.02) (18 men), aged 34–48 years, were enrolled in this study, reaching a similar concentration to normotensive pa- 17 hypertensive never-treated patients (HTA) and 13 tients (3.3370.3 pg/ml) after treatment with irbesartan. normotensive subjects (C). HTA subjects were treated No significant changes were observed in any other of with irbesartan, 150–300 mg/day for 3 months, and the tested parameters. In conclusion, the treatment of serum IL-6, vascular cell adhesion molecule-1, inter- high blood pressure lowers circulating IL-6 in young cellular adhesion molecule-1, sP-selectin, sE-selectin hypertensive patients. and monocyte chemoattractant protein-1 were mea- Journal of Human Hypertension (2005) 19, 457–462. sured at 0 and 12 weeks. The two study groups were doi:10.1038/sj.jhh.1001845 similar in age, body mass index (BMI) and gender. Published online 10 March 2005

Keywords: cytokines; inflammation; irbesartan

Introduction and P-selectin have also been reported to be increased in patients with essential hypertension.3,4 Atherosclerosis is increasingly recognised as an Antihypertensive drugs show different properties inflammatory disease. Interleukin-6 (IL-6) is a multi- not directly related to the primary effect.5 A type 1 functional cytokine produced by many different cell specific angiotensin (AT1) receptor blocker like types, including immune cells, endothelial cells, 1 valsartan led to an improvement of inflammatory fibroblasts, myocytes and adipocytes. vascular injury.6 Losartan also displayed antioxidant IL-6 is one of the major proinflammatory cyto- properties leading to a decreased oxidation rate of kines, having a pivotal role in the inflammatory low-density lipoprotein.7 process involved in atherosclerotic disease. Raised We aimed to explore whether the concentration IL-6 levels and leucocyte adhesiveness have been of the inflammatory markers IL-6, vascular cell found to be associated with increased blood pres- adhesion molecule-1 (VCAM-1), intercellular adhe- sure, linking hypertension to a proinflammatory 2 sion molecule-1 (ICAM-1), sP-selectin, sE-selectin state. Adhesion molecules like soluble E-selectin and monocyte chemoattractant protein-1 (MCP-1) could be modified by decreasing blood pressure in hypertensive patients with irbesartan. Correspondence: Dr G Va´zquez-Oliva, Unitat de Cardiologia, Hospital Comarcal de Blanes y Hospital Comarcal de Calella, Corporacio´ de Salut del Maresme i La Selva, Cala Sant Francesc s/n. 17300 Blanes, Girona, Spain. Patients and methods E-mail: [email protected] Potential conflicts of interest: None. A total of 30 patients were enrolled in this study. Received 29 August 2004; revised 3 December 2004; accepted 14 All subjects were of Caucasian origin and reported January 2005; published online 10 March 2005 that their body weight had been stable for at least Irbesartan lowers interleukin-6 GVa´zquez-Oliva et al 458 3 months before the study. None of the subjects Analytical methods was taking any medication or had any evidence of metabolic disease other than obesity. Thus, we Blood samples were drawn at 08:00–09:00, after an designed a protocol to avoid the influence of any overnight fast, with subjects in seated position, from risk factor other than hypertension. Inclusion criter- the antecubital vein, and were then centrifuged at 1 ia for this group were: (1) absence of clinical 3000 r.p.m. Serum samples were stored at À70 C cardiovascular disease; (2) absence of any systemic until required for assays. disease; (3) absence of any infections in the previous The serum glucose concentration was measured month; (4) normal serum cholesterol levels (defined in duplicate by the glucose oxidase method. Total as cholesterol o6.5 mmol/l); (4) no smoking; (5) no serum cholesterol was measured through the reac- diabetes or fasting glucose o126 mg/dl. tion of cholesterol esterase/cholesterol oxidase/ The patients were subdivided into two groups. peroxidase. Total serum triglycerides were mea- Group 1 included 17 patients with essential hyper- sured through the reaction of glycerol-phosphate- tension (recently diagnosed essential hypertension oxidase and peroxidase. Serum HDL cholesterol with systolic blood pressure (SBP) X140 mmHg, levels were assessed by enzymatic methods (Boeh- diastolic blood pressure (DBP) X90 mmHg), who ringer, Mannheim, Germany), and LDL cholesterol levels were assessed by the method of Friedewald had never received antihypertensive drugs; and 8 group 2 included 13 normotensive patients. et al. Resting blood pressure was measured after sub- Serum IL-6 was measured using a commercial t jects had been in a sitting position for a minimum of immunoassay (MEDGENIX IL-6 EASIA , BioSource 15 min using a mercury sphygmomanometer, and Europe S.A., Zoning Industriel B-6220, Fleunes, was read three times on the right arm by the same Belgium), with coefficients of variation lower than investigator. The mean of the three measurements 6%. VCAM-1, ICAM-1, sP-selectin and sE-selectin was used for this study. All women had regular were measured by enzyme-linked immunosorbent menstrual cycles and were studied in the follicular assay (ELISA) with coefficients of variation of 3, 8, 6 phase of the menstrual cycle. and 5%, respectively (Bender-MedSystem, Vienna, Informed written consent was obtained after the Austria). Assays for MCP-1 were performed with purpose, nature and potential risks of the study were the use of commercially available ELISA kits (R&D explained to the subjects. The experimental protocol Systems, Minneapolis, MN, USA) with coefficient of was approved by the local scientific committee. variation lower than 6%. Fibrinogen was measured t Diagnosis of essential hypertension was estab- by nephelometry with ACL analyst. lished by absence of clinical evidence of secondary hypertension and by normal serum electrolytes, creatinine, urinalysis, abdominal echography, and, Statistical analysis when indicated, renal scintiscan or computed Descriptive results of continuous variables are abdominal tomography. Patients received irbesartan, expressed as mean7standard deviation (s.d.). Be- 150 mg per day, which was increased to 300 mg per fore statistical analysis, normal distribution and day if blood pressure persisted at levels higher than homogeneity of the variances were tested. Para- 140/90 mmHg after the first month. meters that did not fulfil these tests (IL-6, serum The study strength was calculated from a previous triglycerides, fibrinogen) were log transformed. study seeking the relationship of IL-6 with blood 2 Comparisons were performed using paired Student’s pressure. Assuming an alpha risk of 0.05, a beta risk t-test. The relations between variables were ana- of 0.10 and a bilateral test, 13 subjects were needed lysed by simple correlation (Pearson’s and Spear- to detect a difference greater than 0.6 (the standard man’s tests) and multiple regression in a stepwise deviation of IL-6 in control normotensive subjects). manner. Levels of statistical significance were set at A greater number of patients were included to Po0.05. further decrease the alpha and beta risks. The study spanned 12 weeks with serum samples collected at 0 and 12 weeks. One patient renounced Results to follow up. Anthropometric and biochemical characteristics of the subjects at time of entry into the study are shown Anthropometric measurements in Table 1. We included 16 young hypertensive patients (10 men) and 13 control subjects (8 men) BMI was calculated as weight (in kilograms) divided who were comparable in age, BMI, WHR and plasma by height (in metres) squared. The subject’s waist lipids concentration. When all subjects were con- was measured with a soft tape midway between the sidered as a whole (Table 2), baseline IL-6 concen- lowest rib and the iliac crest. The hip circumference tration was significantly associated with SBP was measured at the widest part of the gluteal (r ¼ 0.41; P ¼ 0.03), fibrinogen (r ¼ 0.53; P ¼ 0.005), region. The waist-to-hip ratio (WHR) was then triglycerides (r ¼ 0.50; P ¼ 0.009) and BMI (r ¼ 0.53; calculated. P ¼ 0.005).

Journal of Human Hypertension Irbesartan lowers interleukin-6 GVa´zquez-Oliva et al 459 VCAM-1, ICAM-1, selectin-E, selectin-P and MCP- present in the control, normotensive group. The 1 showed no differences between the two groups. reduction in the IL-6 levels was similar to the Despite the fact that IL-6 tended to be higher in reduction in arterial blood pressure (Figure 1). hypertensive than in control subjects, the differ- Irbesartan produced no change in baseline soluble ences did not reach statistical significance. How- VCAM-1, ICAM-1, sE-selectin, sP-selectin and ever, when the concentration of IL-6 was evaluated MCP-1, which were not raised at baseline in our according to sex, we found that hypertensive HTA patients. No episode of major side effect was women showed significantly increased IL-6 levels registered. compared to control subjects (P ¼ 0.04). Irbesartan treatment decreased blood pressure significantly (SBP, from 151714 to 13078 mmHg; Discussion DBP, from 9676 to 81.875 mmHg) (Table 3). No significant changes in BMI, WHR, plasma lipids or We have previously described that blood pressure serum fibrinogen were observed after treatment. levels have been directly associated with circulating Irbesartan led to significantly decreased circulating IL-6 concentrations in healthy subjects,2 and a IL-6 levels (P ¼ 0.02) reaching similar levels to those significant graded relationship between blood

Table 1 General characteristics of the study population: clinical Table 3 Baseline and follow-up clinical and biochemical vari- and biochemical variables in the study subjects ables in hypertensive patients

Variable Control HTA Variable Baseline Follow-up

N 13 16 N 16 16 7 7 Men/women 8/5 10/6 Age (years) 40.81 7 40.9 7 7 7 Age (years) 41.3178 40.8177 Weight 77.2 15 77.3 15 2 7 7 Weight 7479 77.2715 Body mass index (kg/m ) 28.5 5 28.6 5 7 7 Body mass index (kg/m2) 26.772 28.575 Waist-to-hip ratio 0.89 0.07 0.89 0.08 7 7 Waist-to-hip ratio 0.8770.08 0.8970.07 Systolic blood pressure (mmHg) 151 14 130 8** 7 7 Systolic blood pressure (mmHg) 115.1710 151714** Diastolic blood pressure (mmHg) 96 6 81.8 5** 7 7 Diastolic blood pressure (mmHg) 72789676** Fasting glucose (mmol/l) 5.66 0.77 5.69 0.66 7 7 Fasting glucose (mmol/l) 5.1370.27 5.6670.77* Cholesterol (mmol/l) 4.96 0.95 5.18 1.13 7 7 Cholesterol ((mmol/l) 4.8672.14 4.9670.95 LDL-cholesterol (mmol/l) 3.15 0.75 3.08 0.72 7 7 LDL-cholesterol (mmol/l) 3.3070.75 3.1570.75 HDL-cholesterol (mmol/l) 1.45 0.36 1.45 0.36 7 7 HDL-cholesterol (mmol/l) 1.2670.31 1.4570.36 Triglycerides (mmol/l) 0.848 0.34 0.938 0.45 7 7 Triglycerides (mmol/l) 0.7870.31 0.8470.34 Fibrinogen (mmol/l) 3.50 0.93 3.47 0.61 7 7 Fibrinogen (mmol/l) 3.6870.75 3.5070.93 Interleukin-6 (mg/l) 3.72 0.82 3.23 0.19* 7 7 Interleukin-6 (mg/l) 3.3370.3 3.7270.82 VCAM-1 (mg/l) 800.3 210 834.3 221 7 7 VCAM-1 (mg/l) 965.247276 798.707203 ICAM-1 (mg/l) 261.8 59 249.2 64 7 7 ICAM-1 (mg/l) 249.98752 261.80759 Selectin-E (mg/l) 20.6 9 20.5 9 7 7 Selectin-E (mg/l) 17.91712 20.6379 Selectin-P (mg/l) 79.1 24 97.4 54 7 7 Selectin-P (mg/l) 91.58720 79.18724 MCP-1 (mg/l) 141.01 25 132.40 23 MCP-1 (mg/l) 138.82735 141.01725 The follow-up was performed after treatment with irbesartan for 12 7 LDL, low-density lipoprotein; HDL, high-density lipoprotein; VCAM, weeks. Data expressed as mean values s.d. vascular cell adhesion molecule; ICAM, intercellular adhesion LDL, low-density lipoprotein; HDL, high-density lipoprotein; VCAM, molecule; MCP, monocyte chemoattractant protein. vascular cell adhesion molecule; ICAM, intercellular adhesion Data expressed as mean values7s.d. molecule; MCP, monocyte chemoattractant protein. *P 0.05; **P 0.01. *Po0.05; **Po0.01. o o

Table 2 Correlations in whole group. N ¼ 29 patients

SBP DBP BMI Fibrinogen Col Trg

BMI 0.178 0.326 0.253 0.106 0.672** Fibrinogen 0.131 0.012 0.253 0.162 0.061 Col 0.196 0.134 0.106 0.162 0.136 Trg 0.072 0.176 0.672** 0.061 0.136 VCAM-1 À0.379 À0.311 0.036 0.021 À0.378 0.167 ICAM-1 À0.008 0.135 0.131 À0.152 À0.235 À0.126 Selectin-E 0.222 0.227 À0.231 0.005 0.112 À0.112 Selectin-P À0.309 À0.132 0.016 À0.78 À0.072 À0.072 MCP-1 À0.034 0.089 0.469* 0.037 0.086 0.379 Interleukin-6 0.413* 0.354 0.531** 0.535** 0.233 0.505**

SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; Col, cholesterol; Trg, triglycerides. *Po0.05, **Po0.001.

Journal of Human Hypertension Irbesartan lowers interleukin-6 GVa´zquez-Oliva et al 460 pressure and levels of IL-6 and ICAM-1 has been Experimental data in animal models have shown observed in apparently healthy men.9,10 These an inhibition of the inflammatory component of the conclusions are coincident with our results, since atherosclerotic lesions after treatment with irbesar- in our study we have found a significant relation- tan11 and valsartan.6 In addition to blood pressure, ship between SBP and circulating IL-6 concentra- IL-6 can contribute to atherogenesis in several other tion in a sample of young hypertensive subjects. ways, such as its influence on adhesion molecules, On the other hand, this is the first study to explore by increasing endothelial permeability, promoting the effect of lowering blood pressure with irbesartan vascular smooth muscle cell proliferation or on circulating IL-6 levels in young hypertensive inducing lipid abnormalities.12 IL-6 can also lead patients. We have found that irbesartan led to to increased collagen,13 and raised fibrinogen decreased IL-6 in parallel to lowering of blood synthesis.14 In our study, serum levels of VCAM-1, pressure in a relatively short time period. To our ICAM-1, sE-selectin, sP-selectin and MCP-1 did not knowledge, only few papers (summarised in Table 4) change significantly after therapy with irbesartan. have examined the anti-inflammatory effects of the Although irbesartan has been known to decrease angiotensin receptors blockers. We would like to serum levels of VCAM-115 and MCP-116,17 in experi- emphasise that none of these studies enrolled mental models, Prasad et al18 did not find significant recently diagnosed hypertensive patients, and all changes in VCAM-1 and ICAM-1 after therapy with the studies were performed in patients with asso- losartan in 31 coronary heart disease patients. ciated complications. Recently, Fliser et al19 did not find changes in ICAM-1 after therapy with Olmesartan in 199 patients with essential hypertension and diagnosed 136 3.8 atherosclerotic disease. It is plausible that a longer treatment period or treatment of higher risk patients 135 could influence additional markers. It is important to remark that IL-6 can induce 134 3.6 angiotensinogen expression,20 leading to a higher ** concentration of angiotensin II. Many of the 133 proatherosclerotic effects of angiotensin II are * mediated by binding of the peptide to the AT1 receptor.21 Angiotensin II has been shown to facil- 132 3.4 itate the recruitment of monocytes into the vessel wall by stimulating the production of MCP-1 and 131 VCAM-1 in in vitro cultures of smooth muscle cells and endothelial cells.21,22 Indeed, in vitro data have 130 3.2 shown that the oxidant stress triggered by angiotensin II may contribute to enhanced oxidation of LDL 129 and degradation of nitric oxide, and stimulate the expression of ICAM-123 and IL-6.24 Interestingly, 128 3 IL-6 induces oxidative stress and endothelial dys- Baseline Follow-up function by overexpression of angiotensin II type 1 receptor.25 SBP IL6 Although most of the beneficial effects provided Figure 1 Reduction of the arterial blood pressure and reduction by AT1 blockers appear to be related to blockade of 25 in the IL-6 levels with irbesartan. SBP, systolic blood pressure; IL- AT1 receptor, some positive effects of these drugs 6, interleukin-6. **Po0.01, *Po0.05. could be due to the stimulation of AT2 receptors.

Table 4 Brief review of the articles published on the anti-inflammatory effects of the angiotensin receptor blockers

First author (year) Patients Drug Results P

Fliser19 (2004) 199 p. HBP and AD Olmesartan, pravastatina vs placebo Olmesartan lowered IL-6 levels o0.01 Schieffer26 (2004) 60 p. CAD and HBP Irbesartan vs enalapril Irbesartan lowered IL-6 levels o0.01 Lauten27 (2003) 112 p. CAD and normal BP Irbesartan vs quinapril vs placebo Irbesartan and quinapril lowered o0.05 IL-6 levels Tsutamoto28 (2000) 23 p. CHF and LVEFo45% Candesartan vs placebo Cardesartan lowered IL-6 o0.05 Peeters29 (1998) 23 p. HBP (ex vivo) Valsartan vs captopril No difference in s-IL-6 NS

AD, atherosclerotic disease; CAD, coronary artery disease; HBP, high blood pressure; BP, blood pressure; LVEF, left ventricular ejection fraction; NS, nonsignificant.

Journal of Human Hypertension Irbesartan lowers interleukin-6 GVa´zquez-Oliva et al 461 This stimulation leads to improvement of the inflam- 8 Friedewald WT, Levy R, Frederickson D. Estimation of matory vascular injury, antagonising the effects of the concentration of low-density lipoprotein cholester- angiotensin II on arterial hypertrophy and fibrosis, ol in plasma without use of preparative ultracentrifuge. and inhibiting IL-6 expression.6 Clin Chem 1972; 18: 499–502. A limitation of our study is the relatively small 9 Chae C, Lee R, Rifai N, Ridker P. Blood pressure and inflammation in apparently healthy men. Hyperten- sample size. Although the results suggest an anti- sion 2001; 38: 399–403. inflammatory effect of irbesartan in relation with 10 Bautista LE, Vera LM, Arenas IA, Gamara G. Indepen- decreased arterial blood pressure, further studies dent association between inflammatory markers (C- will be needed in a larger number of patients to reactive protein, interleukin-6 and TNF-a) and essen- confirm these findings. It also remains unclear tial hypertension. J Hum Hypertens, advance online whether lowering of blood pressure by other means publication, Sept. 9 2004; doi:10.1038/sj.jhh.1001785. contributes to the reduction in IL-6. 11 Dol F et al. Angiotensin AT1 receptor antagonist In conclusion, irbesartan seems to act as an anti- irbesartan decreases lesion size, chemokine expres- inflammatory molecule as suggested by the lowering sion, and macrophage accumulation in apolipoprotein of circulating IL-6 levels after 3 months of therapy. E-deficient mice. J Cardiovasc Pharmacol 2001; 38: 395–405. It is possible that a longer treatment period, or 12 Ikeda U et al. Interleukin 6 stimulates growth of using higher risk patients, could influence addi- vascular smooth muscle cells in a PDGF-dependent tional markers. Further studies are needed to manner. Am J Physiol 1991; 260: H1713–H1717. confirm these observations. 13 Greenwel P et al. Induction of an acute phase response in rats stimulates the expression of alpha 1 procollagen messenger ribonucleic acid in their livers. Possible role of interleukin-6. Lab Invest 1995; 72: Acknowledgements 83–91. 14 Lowe GDO, Rumley A. Coagulation, fibrinolysis and We thank Dr J Roca-Antonio and Dr JA Gonza´lez- cardiovascular disease. Fibrinolysis Proteolysis 1999; Ares for statistical and epidemiological analysis. We 13: 91–98. also acknowledge J Massa and Dr I Caballe for her 15 Navalkar S, Parthasarathy S, Santanam N, Khan BV. work in laboratory analysis and A Gibert and E Cata Irbesartan, an angiotensin type 1 receptor inhibitor, for recruitment of patients. 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