NG-Nitro-L-Arginine Methyl Ester, an Inhibitor of Nitric Oxide Synthesis, Ameliorates Interleukin-2-induced Capillary Leak Syndrome in Healthy Mice

We tested whether NG-nitro-L-arginine methyl ester (L-NAME), a potent inhibitor of NO synthesis, can prevent interleukin-2 (IL-2)-induced capillary leakage. Healthy C3H/HeJ female mice were treated with: nothing; IL-2 (10 injections; 35,000, 15,000, or 7,500 Cetus U i.p. every 8 h); IL-2 + L-NAME (0.01, 0.1, 0.5, and 1 mg/ml of drinking water starting 1 day before IL-2 therapy and ending with IL-2 therapy); or L-NAME alone. In the first series of experiments, mice were killed 1 h after last IL-2 injection to measure pleural effusion, and water content of the lungs, spleen, and kidney (markers of capillary leakage), as well as NO2- + NO3- levels in the serum and pleural effusion. In the two additional series, the survival of treated mice was followed. All doses of IL-2-induced capillary leak syndrome as indicated by pleural effusion, pulmonary edema, and fluid retention in the spleen and kidney. NO production was positively correlated with manifestation and severity of this syndrome. NO2- + NO3- levels in the pleural effusion were directly related to IL-2 dose, and L-NAME treatment reduced both the NO production and severity of capillary leakage, excepting fluid retention in the kidney. However, L-NAME therapy prevented IL-2-induced mortality only when combined with a middle range IL-2 dose (15,000 U/injection). In summary, oral L-NAME therapy effectively prevented IL-2-induced capillary leakage in healthy mice, suggesting its potential value as a supplement in IL-2-based immunotherapy of cancer and infectious diseases.