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

Abstract

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.