ANTIPYRETIC ROLE OF NITRIC-OXIDE DURING ENDOTOXIN-INDUCED FEVER IN RABBITS

To investigate the role of nitric oxide (NO) and its interaction with oxygen radicals in fever; we injected conscious rabbits intravenously (i.v.) with 1 mu g/kg bacterial lipopolysaccharide (LPS) and measured body temperatures, and circulatory and respiratory parameters. We esti mated plasma levels of antidiuretic hormone (ADH); nitrate as a measur e of NO metabolism under aerobic conditions; prostaglandin E-2 (PGE(2) ) and prostaglandin PGF(2 alpha) (PGF(2 alpha)); and tumor necrosis fa ctor alpha (TNF alpha). We studied the effects of IFS before and after treatment with oxygen radical scavengers superoxide dismutase and cat alase (SOD/CAT), before and after treatment with N-G-monomethyl-L-argi nine (L-NMMA), a specific blocker of nitric oxide synthase (NOS), befo re acid after treatment with methylene blue (MB). N-methyl-D-aspartate (NMDA) receptors were blocked with kelamine. IFS increased core tempe rature by 1.1 +/- 0.1 degrees C within 3 h, associated with a rapid in crease of plasma TNF alpha PGE(2) and PGF(2 alpha) and a fail of nitra te. The decrease of nitrate following LPS was augmented in rabbits pre treated with SOD/CAT; associated with a rise of core temperature of 1. 6 +/- 0.1 degrees C within 3 h. The lowest levels of nitrate were obse rved in rabbits pretreated with L-NMMA, associated with a rise of core temperature of 3.0 +/- 0.1 degrees C within 3 h. Treating the same ra bbits with a continuous i.v. infusion of 5 mg/kg/h MB, starting 30 min before injection of LPS, caused an immediate increase in nitrate and completely prevented fever The rise of TNF alpha and ADH after LPS, ho wever was not significantly different from the control fever and plasm a PGE(2) levels were nearly twice as elevated. MB also prevented fever in NMMA-treated rabbits, but only as long as nitrate levels remained elevated MB induced an immediate rise of core temperature in ketamine- treated rabbits. We conclude that an undisturbed or elevated synthesis of NO in the central nervous system prevents fever; possibly via posi tive feedback action of NO on presynaptic glutaminergic neurons.