Nitric oxide synthase-cyclo-oxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits

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Abstract
1 . Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001–10 μ) into the organum vasculosum laminae terminalis (OVLT). Deep body temperature was evaluated over a period of 7 h. 2 . The LPS-induced febrile response was mimicked by intra-OVLT injection of the nitric oxide (NO) donors, S-nitroso-acetylpenicillamine (SNAP, 1–10 μ), sodium nitroprusside (SNP, 50 μ), or hydroxylamine (10 μ), the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP, 10–100 μ), or prostaglandin E2 (PGE2, 0.2 μ). 3 . Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 μ), anisomycin (a protein synthesis inhibitor, 100 μ), L-N5-(1-iminoethyl)ornithine (L-NIO; an irreversible NOS inhibitor, 10–200 μ), aminoguanidine (a specific iNOS inhibitor, 1000 μ), or NG-methyl-L-arginine acetate (L-NMMA, a NOS inhibitor, 100 μ) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra-OVLT dose of 1000 μ of NG-nitro-L-arginine methyl ester (L-NAME, a potent inhibitor of constitutive NOS) did not exhibit antipyretic effects. 4 . Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1–10 μ), 6-(phenylamino)-5,8-quinolinedione (LY-83583; an inhibitor of soluble guanylate cyclase and NO release, 20 μ), or indomethacin (an inhibitor of cyclo-oxygenase, COX, 400 μ) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 μ) attenuated the fever induced by intra-OVLT injection of SNAP. 5 . The PGE2-induced fever was potentiated, rather then attenuated, by pretreatment with an intra-OVLT dose of animoguanidine (1000 μ), L-NMMA (100 μ), or L-NIO (200 μ). 6 . These results suggest that iNOS-COX pathways in the OVLT represent an important mechanism for modulation of pyrogenic fever in rabbits.