N-G-METHYL-L-ARGININE, AN INHIBITOR OF NITRIC-OXIDE SYNTHASE, REVERSES INTERLEUKIN-2-INDUCED HYPOTENSION

To evaluate the role of N-G-methyl-L-arginine as a modulator of the hy perdynamic shock induced by the administration of interleukin-2 (IL-2) . Design: A prospective, pilot clinical study. Setting: Intensive care unit of a tertiary care center. Patients: Three sequential patients w ith metastatic renal cell carcinoma who developed hypotension during t heir first course of treatment with high-dose IL-2 (18 x 10(6) IU/m(2) /day by continuous infusion for 5 days). Interventions: Upon developin g hypotension during their subsequent therapy with IL-2, patients were administered 12 mg/kg of N-G-methyl-L-arginine. Thereafter, a dose of 4 mg/kg was given every 4 hrs, as needed, to maintain the systolic bl ood pressure above 100 mm Hg. Measurements and Main Results: Invasive hemodynamic monitoring was instituted before the initiation of treatme nt with IL-2. Differences noted before, and 15 mim after, the administ ration of N-G-methyl-L-arginine were analyzed using the paired t-test. N-G-methyl-L arginine (12 mg/kg) induced a significant antihypotensiv e effect (mean blood pressure increased from 87 +/- 4 to 121 +/- 7 mm Hg), accompanied by an increase of the systemic vascular resistance (5 49 +/- 51 to 860 +/- 167 dyne sec/cm(5)) and pulmonary vascular resist ance (81 +/- 16 to 117 +/- 29 dyne sec/cm(6)). A decrease in the cardi ac index was also documented (4.5 +/- 0.5 to 3.6 +/- 0.3 L/min/m(2)), No significant changes in pulmonary artery occlusion and central venou s pressures were observed, Maintenance doses of 4 mg/kg of N-G-methyl- L-arginine induced similar hemodynamic results, although the duration of the antihypotensive effect of N-G-methyl-l-arginine decreased with sequential doses. Conclusions: The hemodynamic effects induced by IL-2 administration are reversed by N-G-methyl-L-arginine, a nitric oxide synthesis inhibitor. These results provide evidence for the biological activity of N-G-methyl-L-arginine when administered alone to hypotens ive patients. While no adverse effects were observed in this prelimina ry study, issues of toxicity and effectiveness need to be defined furt her in formal clinical trials. N-G-methyl-L-arginine may play a therap eutic role in the modulation of the extreme vasodilation induced by cy tokine administration or in septic shock.