Endothelin-1 as a central mediator of LPS-induced fever in rats

Abstract

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.