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 ETB 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 μg kg−1, i.v.) induced fever which peaked at 1.16 ± 0.24 °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 °C, 3 h), but simultaneously decreased tail skin temperature (−1.10 ± 0.26 °C), indicating cutaneous vasoconstriction. Moreover, endothelin-1 induced fever (1.0 ± 0.3 °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.