PYROGEN - PROSTAGLANDIN COUPLING IN THE PATHOGENESIS OF FEVER - EVIDENCE AGAINST A ROLE FOR NITRIC-OXIDE

There is much debate on the mechanism by which blood-borne pyrogens tr igger prostaglandin E(2) (PGE(2)) synthesis in brain and fever. This i nvestigation was undertaken to determine whether nitric oxide qualifie s as a signal transducer for pyrogens at the interface between blood a nd brain. Experiments were carried out in vitro and in vivo using, res pectively, preparations of cerebral tissue and microvessels from the r at, and the conscious, chronically instrumented cat. In vitro preparat ions produced PGE(2) and its production increased during a 30-min trea tment with interleukin 1 (brain tissue) or endotoxin (microvessels). I n addition, both pyrogens increased cyclic GMP levels in cerebral micr ovessels. In both brain tissue and microvessels, N-G-nitro-L-arginine had no effect on basal PGE(2) release, while it curtailed the pyrogen- stimulated release. The same treatment reduced the cyclic GMP accumula tion brought about by pyrogens in the microvessels. Conversely, in the conscious cat, inhibitors of nitric oxide synthesis (N-G-monomethyl-L -arginine, N-G-nitro-L-arginine) had no effect on fever and the concom itant elevation of PGE(2) in cerebrospinal fluid, regardless of the py rogen used (endotoxin, interleukin 1) and the route of administration (intravenous, intracerebroventricular). We conclude that nitric oxide may serve as a pyrogen mediator in brain. This mediator function, howe ver, is seemingly not important in the development of fever.