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

1 Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001-10 mu g) 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 mu g), sodium nitroprusside (SNP, 50 mu g), or hydroxylamine (10 mu g), the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP, 10-100 mu g), or prostaglandin E(2) (PGE(2), 0.2 mu g). 3 Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 mu g), anisomycin (a protein synthesis inhibitor, 100 mu g), L-N-5-(1-iminoethyl)ornithine (L-NIO; an irreversible NOS inhibitor, 10-200 mu g), aminoguanidine (a specific iNOS inhibitor, 1000 mu g), or N-G-methyl-L-arginine acetate (L-NMMA, a NOS inhibitor, 100 mu g) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra-OVLT dose of 1000 mu g of N-G-nitro-L-arginine methyl ester (L-NAME, a potent inhibitor of constitutive NOS) did nor exhibit antipyretic effects. 4 Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1-10 mu g), 6-(phenylamino)-5,8-quinolinedione (LY-83583; an inhibitor of soluble guanylate cyclase and NO release, 20 mu g), or indomethacin (an inhibitor of cyclo-oxygenase, COX, 400 mu g) inhibited fever induced by LPS when injected into the OVLT I h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 mu g) attenuated the fever induced by intra-OVLT injection of SNAP. 5 The PGE(2)-induced fever was potentiated, rather then attenuated, by pretreatment with an intra-OVLT dose of animoguanidine (1000 mu g), L-NMMA (100 mu g), or L-NIO (200 mu g). 6 These results suggest that iNOS-COX pathways in the OVLT represent an important mechanism for modulation of pyrogenic fever in rabbits.