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 trigger prostaglandin E2 (PGE2) synthesis in brain and fever. This investigation was undertaken to determine whether nitric oxide qualifies as a signal transducer for pyrogens at the interface between blood and brain. Experiments were carried out in vitro and in vivo using, respectively, preparations of cerebral tissue and microvessels from the rat, and the conscious, chronically instrumented cat. In vitro preparations produced PGE2 and its production increased during a 30-min treatment with interleukin 1 (brain tissue) or endotoxin (microvessels). In addition, both pyrogens increased cyclic GMP levels in cerebral microvessels. In both brain tissue and microvessels, NG-nitro-L-arginine had no effect on basal PGE2 release, while it curtailed the pyrogen-stimulated release. The same treatment reduced the cyclic GMP accumulation brought about by pyrogens in the microvessels. Conversely, in the conscious cat, inhibitors of nitric oxide synthesis (NG-monomethyl-L-arginine, NG-nitro-L-arginine) had no effect on fever and the concomitant elevation of PGE2 in cerebrospinal fluid, regardless of the pyrogen 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, however, is seemingly not important in the development of fever.
Redford
J
J
Division of Neurosciences, Research Institute, The Hospital of Sick Children, Toronto, Canada.
Bishai
I
I
Coceani
F
F
D000818:Animals; D002415:Cats; D006152:Cyclic GMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis*; D004731:Endotoxins / Q000494:pharmacology; D005260:Female; D005334:Fever / Q000209:etiology* / Q000378:metabolism; D066298:In Vitro Techniques; D007378:Interleukins / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D011749:Pyrogens / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
D004731:Endotoxins; D007378:Interleukins; D011749:Pyrogens; D011994:Recombinant Proteins; D009569:Nitric Oxide; D006152:Cyclic GMP; D015232:Dinoprostone