No abstract

We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area of conscious guinea pigs evokes a fall in core temperature (Tco) that is mediated by a reduction in metabolic rate. To identify the adrenoceptor subtype(s) involved in this effect, we microdialyzed intrapreoptically various adrenergic agonists or antagonists singly or in combinations. Tco and ear skin temperatures of the animals were monitored throughout the experiments. alpha 1-, beta-, beta 1-, and beta 2-agonists and antagonists did not induce significant Tco changes. Although the alpha 2-antagonists yohimbine (Yoh) and rauwolscine (Rau) did not have thermal effects per se, the alpha 2-agonist clonidine evoked dose-dependent Tco falls that were abolished by codialyzed Yoh and Rau. The microdialysis of NE evoked, as before, a 0.7 +/- 0.2 degrees C Tco fall; it was abolished by the codialyzed alpha-antagonist phentolamine, Yoh, and Rau but not by the beta-antagonist propranolol. No adrenoceptor agonist induced changes in ear skin temperature. These results indicate that the hypothermizing effect of intrapreoptically microdialyzed NE is achieved by a reduction in metabolic heat production, mediated by alpha 2-adrenoceptors.

We reported recently that the complement (C) system may play a role in the febrile response of guinea pigs to intravenous lipopolysaccharide (LPS) administration because C depletion abolished the LPS-induced rise in core temperature (T(c)). The present study was designed to investigate further the relation between C reduction [induced by cobra venom factor (CVF); 20, 50, 100, and 200 U/animal iv] and the fever of adult, conscious guinea pigs produced by LPS injected intravenously (2 microg/kg) or intraperitoneally (8, 16, 32 microg/kg) 18 h after CVF; control animals received pyrogen-free saline. Serum C levels were measured as total hemolytic C activity before and 18 h after CVF injection and expressed as CH(100) units. In other experiments, serum C levels were determined at various intervals after the intravenous and intraperitoneal injections at different doses of LPS alone. LPS produced fevers generally of similar heights but of different onset latencies and durations, depending on the dose and route of administration. CVF caused dose-related reductions in serum C, from approximately 1,136 U to below detection. These reductions proportionately attenuated the fevers induced by intraperitoneal LPS, but not by intravenous LPS. Intravenous and intraperitoneal LPS per se caused reductions in serum C of 25 and 40%, respectively, indicating activation of the C cascade. These decreases were transient, however, occurring early during the febrile rise approximately 30 min after LPS injection. These data thus support the notion that the C system may be critically involved in the febrile response of guinea pigs to systemic, particularly intraperitoneal, LPS.

Although it is generally believed that circulating exogenous pyrogens [e.g., lipopolysaccharides (LPS)] induce fever via the mediation of endogenous pyrogens (EP) such as cytokines, the first of these, tumor necrosis factor-α, is usually not detectable in blood until at least 30 min after intravenous administration of LPS, whereas the febrile rise begins within 15 min after its administration. Moreover, although abundant evidence indicates that circulating LPS is cleared primarily by liver macrophages [Kupffer cells (KC)], these do not secrete EP in immediate response. This would imply that other factors, presumably evoked earlier than EP, may mediate the onset of the febrile response to intravenous LPS. It is well known that blood-borne LPS very rapidly activates the intravascular complement (C) system, some components of which in turn stimulate the quick release into blood of various substances that have roles in the acute inflammatory reaction. KC contain receptors for C components and are in close contact with afferent vagal terminals in the liver; the involvement of hepatic vagal afferents in LPS-induced fever has recently been shown. In this study, we tested the hypothesis that the initiation of fever by intravenous LPS involves, sequentially, the C system and KC. To test this postulated mechanism, we measured directly the levels of prostaglandin E2(PGE2) in the interstitial fluid of the preoptic anterior hypothalamus (POA), the presumptive site of the fever-producing controller, of conscious guinea pigs over their entire febrile course, before and after C depletion by cobra venom factor (CVF) and before and after elimination of KC by gadolinium chloride (GdCl3). CVF and GdCl3 pretreatment each individually attenuated the first of the biphasic core temperature (Tc) rises after intravenous LPS, inverted the second into a Tcfall, and greatly reduced the usual fever-associated increase in POA PGE2. We conclude, therefore, that C activation may indeed be pivotal in the induction of fever by intravenous LPS and that substance(s) generated presumably by KC in almost immediate reaction to the presence of LPS and/or C may transmit pyrogenic signals via hepatic vagal afferents to the POA, where they rapidly induce the production of PGE2 and, hence, fever.

The release of norepinephrine (NE) and prostaglandin E2 (PGE2) in the preoptic-anterior hypothalamus (POA) by systemically administered pyrogens suggests that both substances may mediate the febrile response. To investigate their possible interaction, we measured directly the levels of PGE2 in the extracellular fluid of the POA of conscious guinea pigs microdialyzed intrapreoptically with exogenous NE over the entire course of their febrile response to endotoxin. Acidified and buffered NE (NEa, NEb), artificial cerebrospinal fluid (aCSFa, aCSFb), and vehicle (Veha, Vehb) were tested. All but aCSFb depressed the febrile response to endotoxin. The microdialysis of aCSFa, aCSFb, Veha, Vehb, and NEa did not change basal preoptic PGE2 levels. However, NEb, at a dose that by itself did not affect body temperature (Tb), caused a large elevation in preoptic PGE2. The intravenous injection of endotoxin increased the level of PGE2 in the POA. NEb potentiated this increase, whereas NEa, aCSFa, and Vehb reduced it; Veha reduced it for the first 60 min and enhanced it for the last 90 min of the experiment. Thus these data suggest that the low pH of the NE solute and/or its Veh may confound the observed effects of NE on the Tb and preoptic PGE2 induced by endotoxin. We surmise that this is due to a neurotoxic action of the antioxidants and the acidity of the solution on thermosensitive neurons in the POA. Hence, the results of experiments using exogenous, usually acidified, NE preparations that often also contain additives should be interpreted with caution.