Posthemorrhagic antipyresis: what stage of fever genesis is affected?

It has been shown that hemorrhage leads to a decreased thermal responsiveness to lipopolysaccharide (LPS). The aim of this study was to clarify what stage of fever genesis [production of endogenous pyrogens such as interleukin-1 (IL-1), increase of the prostaglandin E2 (PGE2) concentration in brain tissue, activation of cold-defense effectors] is deficient in posthemorrhagic antipyresis. In adult rabbits, we evaluated the effect of acute hemorrhage (15 ml/kg) on the rectal temperature (Tre) responses to LPS from Salmonella typhi (200 ng/kg iv), ethanol-purified preparation of homologous IL-1 (1 ml from 3.5 x 10(7) cells, 1.5 ml/kg iv), and PGE2 (1 microg, intracisternal injection). The effect of hemorrhage on Tre was also studied in afebrile rabbits, both at thermoneutrality (23 degrees C) and during ramp cooling (to 7 degrees C). The hemorrhage strongly attenuated the biphasic LPS-induced fever (a Tre rise of 0.4 +/- 0.1 instead of 1.2 +/- 0.2 degrees C at the time of the second peak), the monophasic Tre response to IL-1 (by approximately 0.5 degrees C for over 1-5 h postinjection), and the PGE2-induced hyperthermia (0.4 +/- 0.1 vs. 0.9 +/- 0.1 degrees C, maxima). In afebrile animals, the hemorrhage neither affected Tre at thermoneutrality nor changed the Tre response to cold exposure. The data suggest that neither insufficiency of cold-defense effectors nor lack of endogenous mediators of fever (IL-1, PGE2) can be the only or even the major cause of posthemorrhagic antipyresis. We speculate that fever genesis is altered at a stage occurring after the intrabrain PGE2 level is increased but before thermoeffectors are activated.