Fabricio Aline S C, Rae Giles A, D'Orléans-Juste Pedro, Souza Glória E P
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil.
Brain Res. 2005 Dec 20;1066(1-2):92-100. doi: 10.1016/j.brainres.2005.10.037.
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.
通过阻断中枢内皮素ET(B)受体，可显著降低大肠杆菌脂多糖（LPS）诱导的大鼠发热。本研究通过调查致热剂量的LPS对脑脊液（CSF）中大分子内皮素-1和内皮素-1水平以及血浆中内皮素-1水平的影响，探讨内皮素-1作为大鼠发热中枢介质的作用。我们进一步评估了中枢注射内皮素-1引起的体温升高是仅构成体温过高还是真正的综合性发热反应。静脉注射LPS（5μg kg(-1)）可诱导发热，在2小时内达到峰值1.16±0.24℃，并在5小时内保持稳定。LPS注射后3小时，CSF中免疫反应性（ir）大分子内皮素-1水平降至无法检测的水平，注射后5小时仅部分恢复。生理盐水处理的动物CSF中ir-内皮素-1水平无法检测，但LPS处理后3小时达到21.9±5.2 fmol ml(-1)。生理盐水或LPS处理后血浆ir-内皮素-1水平未发生变化。中枢注射内皮素-1（1 pmol，脑室内注射）可导致体温长期升高（0.81±0.17℃，3小时），但同时降低尾部皮肤温度（-1.10±0.26℃），表明皮肤血管收缩。此外，当注入下丘脑前部视前区（100 fmol）时，内皮素-1可诱导发热（1.0±0.3℃，3小时），但静脉注射（1或10 pmol）则不会。这些数据表明，内皮素-1在大脑中产生，并作为LPS诱导发热的中枢介质发挥作用。
