Recent studies have demonstrated that proinflammatory
cytokines induce large amounts of
nitric oxide (NO) and that the amount increases in patients with
congestive heart failure (CHF). There are, however, few reports regarding the relationships between NO production,
cytokines and the severity of
heart failure, so the plasma concentrations of
nitrite and
nitrate (NOx),
tumor necrosis factor-alpha (
TNF-alpha) and
brain natriuretic peptide (BNP) were measured in 43 patients with CHF caused by
dilated cardiomyopathy and 26 age- and sex-matched normal control subjects. Forearm blood flow (FBF) was measured using plethysmography during infusions of
acetylcholine and
nitroglycerin and after the administration of the NO synthesis inhibitor
L-NMMA (N(G)-monomethyl-
L-arginine). Plasma concentrations of both NOx and
TNF-alpha were significantly higher in the patient group than in the control group (p<0.001) and correlated closely with BNP concentrations (p<0.001). There was a positive relationship between NOx and
TNF-alpha concentrations (r=0.80, p<0.001). Administration of
L-NMMA significantly reduced FBF in both groups, and the percent change in FBF from baseline correlated significantly with
TNF-alpha concentrations (r=0.63, p<0.001). The FBF response to
acetylcholine was depressed in the patient group and correlated inversely with
TNF-alpha concentrations. The FBF response to
nitroglycerin did not correlate with
TNF-alpha concentrations. The findings indicate that the concentrations of NO and
TNF-alpha in patients with CHF increase in proportion to the severity of
heart failure, and that
TNF-alpha plays a role in the enhanced systemic and local production of NO.