Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action.

In view of the pro-oxidant and proinflammatory effects of angiotensin II, we have tested the hypothesis that valsartan, an angiotensin receptor blocker, may exert a suppressive action on reactive oxygen species (ROS) generation, nuclear factor kappa B (NF-kappa B) in mononuclear cells. Four groups of eight normal subjects were given 1) 160 mg daily of valsartan, 2) 80 mg daily of simvastatin, 3) 40 mg quinapril, or 4) no treatment. Fasting blood samples were obtained before treatment and at d 1, 8, and 14 (7 d after the cessation of the drug). After valsartan, ROS generation by polymorphonuclear cells and mononuclear cells fell significantly by more than 40% (P < 0.01). NF-kappa B binding activity and the expression of total cellular p65, a protein component of NF-kappa B, fell significantly (P < 0.01). The expression of inhibitor kappa B (I kappa B) increased significantly (P < 0.05). Plasma C-reactive protein (CRP) concentration fell significantly (P < 0.01). All indices, except I kappa B, reverted toward baseline, 7 d after the cessation of the drug. I kappa B persisted in an elevated state. Neither quinapril nor simvastatin given for 7 d produced a suppression of ROS generation, intranuclear NF-kappa B, p65, or CRP, and these two agents did not alter cellular I kappa B either. The untreated controls also did not demonstrate a change in their ROS generation or NF-kappa B binding activity or plasma CRP concentration. We conclude that valsartan at a modest dose exerts a profound and rapid ROS and inflammation-suppressive effect that may be relevant to its potential beneficial effects in atherosclerosis, diabetes, and congestive cardiac failure. In contrast, quinapril and simvastatin produced no similar effect over the period of 1 wk. Our observations may also have implications to clinical situations in which a rapid antiinflammatory effect is required.

[1]  M. Mercuri,et al.  Effects of simvastatin on C-reactive protein in mixed hyperlipidemic and hypertriglyceridemic patients. , 2002, The American journal of cardiology.

[2]  Steven Snapinn,et al.  Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol , 2002, The Lancet.

[3]  N Rifai,et al.  Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. , 2001, JAMA.

[4]  Richard T. Lee,et al.  Biomechanical Strain Induces Class A Scavenger Receptor Expression in Human Monocyte/Macrophages and THP-1 Cells: A Potential Mechanism of Increased Atherosclerosis in Hypertension , 2001, Circulation.

[5]  A. Aljada,et al.  Nuclear Factor-κB Suppressive and Inhibitor-κB Stimulatory Effects of Troglitazone in Obese Patients with Type 2 Diabetes: Evidence of an Antiinflammatory Action?1 , 2001 .

[6]  A. Aljada,et al.  Insulin Inhibits Intranuclear Nuclear Factor κB and Stimulates IκB in Mononuclear Cells in Obese Subjects: Evidence for an Anti-inflammatory Effect? , 2001 .

[7]  Paul M. Ridker,et al.  Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. , 2001, The New England journal of medicine.

[8]  D. Waters,et al.  PRINCE's prospects: statins, inflammation, and coronary risk. , 2001, American heart journal.

[9]  M. Cooper,et al.  Vascular expression of angiotensin type 2 receptor in the adult rat: influence of angiotensin II infusion , 2001, Journal of hypertension.

[10]  A. Aljada,et al.  Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. , 2001, The Journal of clinical endocrinology and metabolism.

[11]  A. Aljada,et al.  Nadolol inhibits reactive oxygen species generation by leukocytes and linoleic acid oxidation. , 2000, The American journal of cardiology.

[12]  T. Taniguchi,et al.  Participation of Reactive Oxygen Intermediates in the Angiotensin II‐Activated Signaling Pathways in Vascular Smooth Muscle Cells , 2000, Annals of the New York Academy of Sciences.

[13]  R. Carey,et al.  Update: Role of the angiotensin type-2 (AT2) receptor in blood pressure regulation , 2000, Current hypertension reports.

[14]  W. Gonzalez,et al.  Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[15]  S. Yusuf,et al.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. , 2000 .

[16]  A. Aljada,et al.  Carvedilol inhibits reactive oxygen species generation by leukocytes and oxidative damage to amino acids. , 2000, Circulation.

[17]  A. Aljada,et al.  Hydrocortisone-induced inhibition of reactive oxygen species by polymorphonuclear neutrophils. , 1999, Critical care medicine.

[18]  A. Aljada,et al.  Increased IκB Expression and Diminished Nuclear NF-κB in Human Mononuclear Cells following Hydrocortisone Injection , 1999 .

[19]  R. Alexander,et al.  Reactive Oxygen Species Mediate the Activation of Akt/Protein Kinase B by Angiotensin II in Vascular Smooth Muscle Cells* , 1999, The Journal of Biological Chemistry.

[20]  R. Ross,et al.  Atherosclerosis is an inflammatory disease. , 1998, American heart journal.

[21]  M. Karin,et al.  Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. , 1997, The New England journal of medicine.

[22]  David Baltimore,et al.  NF-κB: Ten Years After , 1996, Cell.

[23]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[24]  W. Pearce,et al.  Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response. , 1990, The American journal of pathology.

[25]  A. Baldwin,et al.  THE NF-κB AND IκB PROTEINS: New Discoveries and Insights , 1996 .

[26]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[27]  M. Grilli,et al.  NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. , 1993, International review of cytology.

[28]  E. Ritz,et al.  Specific angiotensin binding to human blood cells. , 1983, Proceedings of the European Dialysis and Transplant Association. European Dialysis and Transplant Association.