Role of prostaglandin E in the biphasic fever response to endotoxin

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Abstract
Biphasic fevers were induced in sheep with intravascular infusions or injections of 4-10 .mu.g (80-200 ng/kg) of endotoxin, whereas monophasic fevers were obtained with doses of 1-2 .mu.g (20-40 ng/kg). A marked increase in arterial blood pressure invariably accompanied the onset of fever; the latency of responses to the higher and lower doses of endotoxins averaged 26 min and 42 min, respectively. Prostaglandin (PG) assays of plasma from the carotid artery and jugular vein during fever episodes revealed a surge of PGE and PGF coincident with the pressor response and the 1st phase of fever, but PG were not detected in plasma samples taken throughout the 2nd phase of fever. PG measurements of arterial and venous plasma collected at a distal site (hind limb) showed a similar surge of PGE and PGF in association with the early fever response, indicating that intravascular PG synthesis and release represents a generalized systemic response to circulating endotoxin. Carotid arterial infusions of PGE2 produced immediate monophasic fevers and pressor responses, whereas PGD2 infusions produced an immediate pressor effect but no fever. Infusions of PGF2.alpha. or prostacyclin evoked neither fever nor pressor effects. Intracarotid infusions of leukocyte pyrogen (LP) caused monophasic fevers with latent periods of 15-20 min but pressor responses were not seen and neither PGE nor PGF were detected in plasma samples from the carotid artery or jugular vein before or during fever. Indomethacin, a potent inhibitor of arachidonic acid metabolism, blocked fever responses to endotoxin and to LP. Thus, PGE was implicasted as the mediator of the early phase of endotoxin fever; a role for another pyrogenic metabolite of arachidonic acid in the mediation of the 2nd phase of fever, i.e., the phase associated with circulating LP, was also implied. It is possible that both pyrogenic metabolites are generated within the vascular compartment, reaching thermoregulatory centers of the brain by transfer across the blood-brain interface.