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Intravascular injections or infusions of moderate doses of bacterial pyrogens are known to produce biphasic fevers, whereas minimal doses elicit monophasic fevers (1, 2). Pyrogen injections into various areas of the brain generally result in monophasic fevers, although recently, biphasic fever has been observed after injections of bacterial pyrogens into the anterior hypothalamic, preoptic region (3). Although it is known that the second phase of fever is associated temporally with circulating leukocyte pyrogen, host mechanisms responsible for the two phases of the biphasic response are not understood (1,4).A large body of evidence has accumulated recently that supports the view that prostaglandin E (PGE)I is a primary mediator of fevers induced by bacterial pyrogens (5-8). Fevers evoked by injections of enteric bacteria either into the third ventricle or proximate to the anterior hypothalamus of the cat (9) are associated with increased PGE levels in cerebrospinal fluid (CSF). Fever, as well as PGE concentrations in CSF, decrease after treatment of febrile animals with ant ipyretic compounds (3, 10) known to inhibit prostaglandin synthesis (11). Additional supportive evidence (6, 12) shows that direct injections of E prostaglandins into the cerebral ventricles of cats and rabbits elicit abrupt, monophasic fevers.More recently, however, the view that PGE is the principal mediator of fever induced by leukocyte pyrogen (LP) has been challenged by Cranston et al. (13,14), who effectively dissociated PGE levels in CSF from the fever response to intravenous infusions of LP. They also found that, although intraventricular injections of PG antagonists together with PGE attenuated fever, little or no change in fever response resulted when these antagonists were injected simultaneously with LP. Other recent evidence (15) casts doubt on the role of PGE in both endotoxin and LP-induced fevers because pretreatment of rabbits with cycloheximide prevented fever in rabbits, even though PGE concentrations in CSF increased to the levels attained in febrile animals not treated with the protein synthesis inhibitor. However, a clear interpretation of the latter experiment is complicated by the fact that cycloheximide alone caused a significant decrement in the core temperature of test animals.We investigated fever responses in the sheep after the intravascular administration of endotoxin and LP with the objective of determining whether PGE or certain other oxidation products of arachidonic acid participate in the fever reaction. Part of this work has been presented elsewhere (16).

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