ASSOCIATION OF MICROVASCULAR LEAKAGE WITH INDUCTION OF NITRIC-OXIDE SYNTHASE - EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITORS IN VARIOUS ORGANS

Endotoxin (Escherichia coli lipopolysaccharide 0111:B4, 3 mg/kg i.v.) induced the expression of a calcium-independent nitric oxide (NO) synt hase, determined after 5 h in cardiac, hepatic, pulmonary and renal ti ssues, as assessed by the conversion of radiolabelled L-arginine to L- citrulline. This widespread induction of NO synthase in these consciou s rats was associated with microvascular injury, as assessed by the va scular leakage of radiolabelled human serum albumin. Concurrent admini stration of the NO synthase inhibitor, N-G-nitro-L-arginine methyl est er (L-NAME, 1-5 mg/kg s.c.) with endotoxin, provoked acute vascular le akage within 2 h in the various organs. By contrast, the delayed injec tion of L-NAME (1-5 mg/kg s.c.) or N-G-monomethyl-L-arginine (12.5-50 mg/kg s.c.) until 3 h after endotoxin challenge inhibited the subseque nt microvascular leakage in these organs. These effects of NO synthase inhibitors were reversed by L-arginine (300 mg/kg s.c.) pretreatment. These results support a protective role of constitutive NO synthase i n the early phase of endotoxin shock. Such actions contrast with the a ggressive actions of the products of inducible NO synthase in the deve lopment of widespread microvascular injury in endotoxemic states.