Conscious cats were used to study the effects of
endotoxin and
interleukin 1 (IL 1) on levels of
prostaglandin (PG) E2 and
thromboxane (TX) B2 (the stable TXA2 byproduct) in cerebrospinal fluid (CSF) from the third ventricle.
Pyrogens were given intravenously or intraventricularly and
prostanoids were measured by radioimmunoassay.
PGE2 was normally less abundant than TXB2 (mean, 37 vs. 528 pg/ml), and its level increased severalfold during the sustained
fever following intravenous
endotoxin (bolus) or IL 1 (bolus plus infusion).
PGE2 elevation preceded the
fever and was maintained thereafter. Likewise, intraventricular
pyrogens promoted
PGE2 formation, and their effect was also manifest during the latent period of the
fever. The
PGE2 metabolite,
13,14-dihydro-15-keto-PGE2, was not measurable in CSF from either afebrile or febrile animals. Basal content of
PGE2, on the other hand, was higher in animals pretreated with
probenecid (30 mg/kg ip or iv; 50 or 100 micrograms ivt), confirming the importance of transport processes in removing
prostanoids from brain. Unlike
PGE2, TXB2 levels did not change during the
fever to intravenous
endotoxin. TXB2 rose instead in response to intraventricular
endotoxin, although the elevation did not extend beyond
fever uprise. Furthermore, a TXA2 analog (
ONO-11113;2 or 4 micrograms ivt) had inconsistent effects on body temperature, while a TXA2 antagonist (
ONO-11120;2 micrograms ivt) did not interfere with
endotoxin fever. These findings strongly support a causative role for
PGE2 in the onset and progression of
pyrogen fever. No evidence of a similar role was obtained for TXA2.