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 hyperdynamic 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 with metastatic renal cell carcinoma who developed hypotension during their 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 developing 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 blood pressure above 100 mm Hg. Measurements and Main Results: Invasive hemodynamic monitoring was instituted before the initiation of treatment with IL-2. Differences noted before, and 15 mim after, the administration of N-G-methyl-L-arginine were analyzed using the paired t-test. N-G-methyl-L arginine (12 mg/kg) induced a significant antihypotensive effect (mean blood pressure increased from 87 +/- 4 to 121 +/- 7 mm Hg), accompanied by an increase of the systemic vascular resistance (549 +/- 51 to 860 +/- 167 dyne sec/cm(5)) and pulmonary vascular resistance (81 +/- 16 to 117 +/- 29 dyne sec/cm(6)). A decrease in the cardiac 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 venous 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 hypotensive patients. While no adverse effects were observed in this preliminary study, issues of toxicity and effectiveness need to be defined further in formal clinical trials. N-G-methyl-L-arginine may play a therapeutic role in the modulation of the extreme vasodilation induced by cytokine administration or in septic shock.