Endothelin-1 as a central mediator of LPS-induced fever in rats.
Fever induced by E. coli lipopolysaccharide (LPS) in rats is substantially reduced by blockade of central endothelin ET(B) receptors. This study explores the role of endothelin-1 as a central mediator of fever in rats, by investigating the effect of a pyrogenic dose of LPS on the levels of big endothelin-1 and endothelin-1 in the cerebrospinal fluid (CSF) and endothelin-1 in the plasma. We further assessed whether the increase in body temperature caused by central injection of endothelin-1 constitutes solely a hyperthermia or a true integrated febrile response. LPS (5 mug kg(-1), i.v.) induced fever which peaked at 1.16 +/- 0.24 degrees C within 2 h and remained stable up to 5 h. CSF levels of immunoreactive (ir) big endothelin-1 decreased to undetectable levels at 3 h after LPS, returning only partially at 5 h post-injection. CSF ir-endothelin-1 levels were undetectable in saline-treated animals, but reached 21.9 +/- 5.2 fmol ml(-1) at 3 h after LPS treatment. Plasma ir-endothelin-1 levels were unchanged after saline or LPS. Central injection of endothelin-1 (1 pmol, i.c.v.) caused long-lasting increases in body temperature (0.81 +/- 0.17 degrees C, 3 h), but simultaneously decreased tail skin temperature (-1.10 +/- 0.26 degrees C), indicating cutaneous vasoconstriction. Moreover, endothelin-1 induced fever (1.0 +/- 0.3 degrees C, 3 h) when injected into the preoptic area of the anterior hypothalamus (100 fmol), but not i.v. (1 or 10 pmol). These data suggest that endothelin-1 is produced in the brain and acts centrally as a mediator of LPS-induced fever.
Fabricio
Aline S C
AS
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil.
Rae
Giles A
GA
D'Orléans-Juste
Pedro
P
Souza
Glória E P
GE
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D019332:Endothelin-1 / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D005334:Fever / Q000139:chemically induced* / Q000503:physiopathology*; D007275:Injections, Intravenous; D008070:Lipopolysaccharides; D008297:Male; D008845:Microinjections; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011301:Preoptic Area / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012881:Skin Temperature / Q000187:drug effects
D000959:Antihypertensive Agents; D019332:Endothelin-1; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010880:Piperidines; C086539:BQ 788