cyclic-gmp and Fever

During systemic inflammation, body temperature is either increased (fever) or decreased (anapyrexia). Either response depends on the dose of the inflammatory agent, e.g., lipopolysaccharide (LPS), and on the ambient temperature. Under thermoneutrality, LPS always produces fever; under subthermoneutral conditions, LPS evokes fever at lower doses and anapyrexia at higher doses. Because of the diagnostic and adaptive values of these responses, understanding their mechanisms is of interest. Recently, the intracellular mechanisms that occur in the preoptic region (PO), the thermointegrative site of the brain, to produce fever and anapyrexia have begun to be clarified. In response to febrigenic doses of LPS, an increased production of prostaglandin E2 and an inhibition of nitric oxide synthesis produce fever respectively by decreasing the intracellular content of cyclic AMP (cAMP) and cyclic GMP (cGMP) in the PO. Although the role of preoptic cAMP and cGMP has not been directly assessed in the anapyrexia induced by LPS, it has been studied in that induced by hypoxia. The likeness between the thermoregulatory responses to hypoxia and to a high dose of LPS suggests that they may have similar mechanisms. In contrast to fever, hypoxia-induced anapyrexia seems to be mediated by a simultaneous increase in the levels of cAMP and cGMP in the PO as the result of an enhanced production and/or release of serotonin and nitric oxide, respectively. This article reviews the recent advances in the understanding of the role of preoptic cAMP and cGMP signaling cascades in fever and anapyrexia.

Topics: Animals; Cyclic AMP; Cyclic GMP; Fever; Humans; Inflammation; Signal Transduction

In spite of considerable research attention focused on clarifying the mechanisms by which the mammalian respiratory rhythm is generated, little attention has been given to examining how this neuronal circuit can be protected from heat stress. Hyperthermia has a profound effect on neuronal circuits including the circuit that generates breathing in mammals. As temperature of the brainstem increases, respiratory frequency concomitantly rises. If temperature continues to increase respiratory arrest (apnea) and death can occur. Previous research has implicated protein kinase G (PKG) activity in regulating neuronal thermosensitivity of neuronal circuits in invertebrates. Here we examine if pharmacological manipulation of PKG activity in a brainstem slice preparation could alter the thermosensitivity of the fictive neonatal mouse respiratory rhythm. We report a striking effect following alteration of PKG activity in the brainstem such that slices treated with the PKG inhibitor KT5823 recovered fictive respiratory rhythm generation significantly faster than control slices and slices treated with a PKG activator (8-Br-cGMP). Furthermore, slices treated with 8-Br-cGMP arrested fictive respiration at a significantly lower temperature than all other treatment groups. In a separate set of experiments we examined if altered PKG activity could regulate the response of slices to hypoxia by altering the protective switch to fictive gasping. Slices treated with 8-Br-cGMP did not switch to the fictive gasp-like pattern following exposure to hypoxia whereas slices treated with KT5823 did display fictive gasping. We propose that PKG activity inversely regulates the amount of stress the neonatal mammalian respiratory rhythm can endure.

Topics: Action Potentials; Animals; Animals, Newborn; Brain Stem; Carbazoles; Cell Hypoxia; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Fever; In Vitro Techniques; Mice; Mice, Inbred Strains; Microelectrodes; Neurons; Periodicity; Protein Kinase Inhibitors; Respiration; Temperature

Nitric oxide has been reported to modulate fever in the brain. However, the sites where NO exerts this modulation remain somewhat unclear. Locus coeruleus (LC) neurons express not only nitric oxide synthase (NOS) but also soluble guanylyl cyclase (sGC). In the present study, we evaluated in vivo and ex vivo the putative role of the LC NO-cGMP pathway in fever. To this end, deep body temperature was measured before and after pharmacological modulations of the pathway. Moreover, nitrite/nitrate (NOx) and cGMP levels in the LC were assessed. Conscious rats were microinjected within the LC with a non-selective NOS inhibitor (N(G)-monomethyl-l-arginine acetate), a NO donor (NOC12), a sGC inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) or a cGMP analogue (8-bromo-cGMP) and injected intraperitoneally with endotoxin. Inhibition of NOS or sGC before endotoxin injection significantly increased the latency to the onset of fever. During the course of fever, inhibition of NOS or sGC attenuated the febrile response, whereas microinjection of NOC12 or 8-bromo-cGMP increased the response. These findings indicate that the LC NO-cGMP pathway plays a propyretic role. Furthermore, we observed a significant increase in NOx and cGMP levels, indicating that the febrile response to endotoxin is accompanied by stimulation of the NO-cGMP pathway in the LC.

Topics: Animals; Cyclic GMP; Endotoxins; Fever; Guanylate Cyclase; Locus Coeruleus; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroso Compounds; Oxadiazoles; Quinoxalines; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Carbon monoxide (CO) has been identified as a diffusible signaling messenger in the brain, capable of altering body temperature by stimulating soluble guanylate cyclase (sGC). However, its site of action remains unclear. Locus coeruleus (LC) is rich not only in sGC but also in heme oxygenase (HO; the enzyme that catalyses the metabolism of heme to CO, along with biliverdin and free iron). Therefore, the possible role of the HO-CO-cGMP pathway in the lipopolysaccharide (LPS)-induced fever regulation by LC neurones was investigated. Induction of the HO pathway using heme-lysinate (7.6 nmol, intra-LC) attenuated the febrile response, and this effect could be prevented by pretreatment with ODQ (an sGC inhibitor; given intracerebroventricularly, 1.3 nmol). Moreover, ZnDPBG (an HO inhibitor; 5 nmol, intra-LC) augmented the febrile response. Taken together, these data suggest that CO in the LC produced by the HO pathway and acting via cGMP plays an antipyretic role during LPS-fever in rats.

Topics: Animals; Body Temperature; Carbon Monoxide; Central Nervous System; Cyclic GMP; Enzyme Inhibitors; Fever; Guanylate Cyclase; Heme; Heme Oxygenase (Decyclizing); Lipopolysaccharides; Locus Coeruleus; Lysine; Male; Rats; Rats, Wistar; Signal Transduction

Recently, heme oxygenase-carbon monoxide (HO-CO) pathway has been reported to be involved in the development of lipopolysaccharide (LPS) fever. However, no information exists about its participation in LPS tolerance, which is defined by an attenuation of the febrile response to repeated administrations of LPS. Thus, we tested the hypothesis that HO-CO pathway plays a role in endotoxin tolerance, which was induced by means of three consecutive LPS intraperitoneal injections (i.p.) at 24-h intervals. Body temperature (Tb) was measured by biotelemetry. Induction of the HO pathway using intracerebroventricular (i.c.v.) heme lysinate reversed tolerance, and this effect could be prevented by pretreatment with ODQ [a soluble guanylate cyclase (sGC) inhibitor; i.c.v.]. These results indicate that HO-CO pathway seems to be down-regulated during LPS tolerance, and that CO is the HO product that can prevent LPS tolerance, acting via cGMP. In further support, either biliverdine or iron (the others HO products; i.c.v.) had no effect in LPS-induced tolerance.

Topics: Animals; Biliverdine; Body Temperature; Carbon Monoxide; Chlorides; Cyclic GMP; Disease Models, Animal; Down-Regulation; Drug Tolerance; Endotoxins; Enzyme Inhibitors; Ferric Compounds; Fever; Guanylate Cyclase; Heme Oxygenase (Decyclizing); Infections; Inflammation Mediators; Injections, Intraperitoneal; Iron; Lipopolysaccharides; Male; Rats; Rats, Wistar; Signal Transduction

It has been shown that the NO pathway plays a major role in restraint stress-induced fever, and that the neuronal nitric oxide synthase (nNOS) seems to be the NOS isoform that accounts for the pyretic effect of NO in psychological stress-induced fever. However, no information exists as to localization of the nNOS, i.e., in the peripheral or in the central nervous system (CNS). Thus, in the present study, we tested the hypothesis that NO arising from nNOS in the CNS participates in restraint stress-induced fever. Moreover, we also assessed the involvement of cyclic guanosine monophosphate (cGMP) in the mediation of the NO effects. To this end, intracerebroventricular S-methyl-L-thiocitrulline (SMTC; a selective nNOS inhibitor), sodium nitroprusside (an NO donor) or Rp-guanosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cGMPS; a specific membrane-permeable inhibitor of the activation by cGMP of cGMP-dependent protein kinase) were injected, and the colonic temperature (T(c)) of restrained or unrestrained rats was recorded. Both SMTC (0.5 mg/mul) and Rp-cGMPS (10 mug/mul) intracerebroventricular injections enhanced restraint fever, whereas intracerebroventricular injections of sodium nitroprusside (100 mug/mul) reduced this response. These data indicate that NO produced in the CNS, arising from nNOS and acting via cGMP, plays an antipyretic role in the restraint stress-induced fever.

Topics: Adaptation, Physiological; Animals; Body Temperature Regulation; Cyclic GMP; Fever; Immobilization; Male; Neurons; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Signal Transduction; Stress, Physiological

We tested the hypothesis that nitric oxide (NO) acts in the anteroventral preoptic region (AVPO) modulating fever. To this end, body core temperature (T(c)) of rats was monitored by biotelemetry before and after pharmacological modulation of the NO pathway. Nitrite/nitrate and cGMP in the anteroventral third ventricular region (AV3V), where the AVPO is located, were also determined. Intra-AVPO microinjection of the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 12.5 microg) did not affect basal T(c), but it enhanced the early stage of lipopolysaccharide (LPS) fever, indicating that NO plays an antipyretic role in the AVPO. In agreement, intra-AVPO microinjection of the NO donor sodium nitroprusside (5 microg) reduced T(c). The antipyretic effect of NO seems to be mediated by cGMP because 1) NO has been shown to activate soluble guanylate cyclase, 2) intra-AVPO microinjection of 8-bromo-cGMP (8-BrcGMP) reduced T(c), and 3) the changes in AV3V levels of nitrite/nitrate and cGMP were similar in the course of fever. Additionally, we observed that nitrite/nitrate and cGMP levels decreased in the AV3V after, but not before, the onset of LPS fever, showing that the activity of the NO-cGMP pathway is reduced in the AV3V after intraperitoneal LPS, a mechanism that could contribute to the genesis and maintenance of fever. It was also observed that the efficacy of 8-BrcGMP in reducing T(c) in the AVPO is increased after LPS, emphasizing that the NO-cGMP pathway is antipyretic. This response could explain why intra-AVPO L-NMMA enhanced the early stage of LPS fever, even though the activity of the NO pathway before the onset of fever was unchanged. In summary, these data support an antipyretic role of the NO-cGMP pathway in the AVPO.

Topics: Animals; Cyclic GMP; Enzyme Inhibitors; Fever; Injections, Intraperitoneal; Lipopolysaccharides; Male; Microinjections; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Nitroprusside; omega-N-Methylarginine; Preoptic Area; Rats; Rats, Wistar; Solubility

Recently, we have reported that the heme oxygenase (HO)-carbon monoxide (CO) pathway plays an important role in the genesis of LPS fever, acting through a cGMP signaling pathway in the brain, but the site of action remains unclear. Thus, the present study was designed to test the hypothesis that the HO-CO pathway mediates fever by acting on the preoptic region of the anterior hypothalamus (POA), which is the brain body core temperature (T(c)) controller site. To this end, the T(c) of rats was monitored by biotelemetry before and after pharmacological modulation of the HO-CO pathway. It was observed that intra-POA administration of the HO inhibitor ZnDPBG (5 nmol) produced no thermoregulatory effect and did not affect LPS (100 microg/kg, i.p.) fever compared to the group treated with the ZnDPBG vehicle, indicating that the HO-CO pathway in the POA is not involved in fever. In agreement, intra-POA heme-lysinate (3.8 or 7.6 nmol), which is known to induce the HO-CO pathway, evoked no change in T(c) compared to the vehicle-treated group. In summary, the present results support the idea that the POA is not the brain site where the HO-CO pathway acts as a fever mediator.

Topics: Animals; Carbon Monoxide; Cyclic GMP; Deuteroporphyrins; Endotoxemia; Enzyme Inhibitors; Fever; Heme; Heme Oxygenase (Decyclizing); Injections, Intraventricular; Lipopolysaccharides; Lysine; Male; Methylene Blue; Microinjections; Preoptic Area; Rats; Rats, Wistar; Vasodilator Agents

The present study aimed to test the hypothesis that a decrease in preoptic cAMP mediates fever. To this end, body core temperature (T(c)) of unanesthetized, freely moving rats was monitored by biotelemetry before and after pharmacological modulation of the cAMP pathway, and cAMP levels in the anteroventral third ventricular region (AV3V), where the preoptic region (POA) is located, were determined. We observed that intra-POA administration of the cAMP agonist dibutyryl-cAMP (Db-cAMP, 40 microg) reduced T(c). PGE(2) (the proximal mediator of fever, 200 ng) raised T(c) with a concomitant decrease in AV3V cAMP levels from 22.7+/-1.8 to 17.0+/-1.0 fmol/microg protein. Moreover, PGE(2)-induced fever was impaired by the phosphodiesterase inhibitor aminophylline. In order to verify the interaction between the cAMP- and cGMP-dependent pathways in the POA, we then co-injected Db-cAMP and 8-Br-cGMP into the POA. As a result, 8-Br-cGMP augmented the drop in T(c) evoked by Db-cAMP. Lastly, we observed that intra-POA co-microinjection of the protein kinase A inhibitor (Rp-cAMPS, 1 microg) with the protein kinase G inhibitor (Rp-cGMPS, 1 microg), mimicking the effects of reduced production of cAMP and cGMP, respectively, produced a fever-like response. In summary, the present data support that a decrease in the levels of cAMP and cGMP in the POA is associated with the genesis of fever.

Topics: Aminophylline; Animals; Body Temperature Regulation; Bucladesine; Cyclic AMP; Cyclic GMP; Dinoprostone; Drug Interactions; Fever; Injections, Intraventricular; Lipopolysaccharides; Male; Microinjections; Neurons; Preoptic Area; Rats; Rats, Wistar; Second Messenger Systems; Thionucleotides

1. Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001-10 micrograms) into the organum vasculosum laminae terminalis (OVLT). Deep body temperature was evaluated over a period of 7 h. 2. The LPS-induced febrile response was mimicked by intra-OVLT injection of the nitric oxide (NO) donors, S-nitroso-acetylpenicillamine (SNAP, 1-10 micrograms), sodium nitroprusside (SNP, 50 micrograms), or hydroxylamine (10 micrograms), the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP, 10-100 micrograms), or prostaglandin E2 (PGE2, 0.2 micrograms). 3. Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 micrograms), anisomycin (a protein synthesis inhibitor, 100 micrograms), L-N5-(1-iminoethyl)ornithine (L-NIO; an irreversible NOS inhibitor, 10-200 micrograms), aminoguanidine (a specific iNOS inhibitor, 1000 micrograms), or NG-methyl-L-arginine acetate (L-NMMA, a NOS inhibitor, 100 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra-OVLT dose of 1000 micrograms of NG-nitro-L-arginine methyl ester (L-NAME, a potent inhibitor of constitutive NOS) did not exhibit antipyretic effects. 4. Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1-10 micrograms), 6-(phenylamino)-5,8-quinolinedione (LY-83583; an inhibitor of soluble guanylate cyclase and NO release, 20 micrograms), or indomethacin (an inhibitor of cyclo-oxygenase, COX, 400 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 micrograms) attenuated the fever induced by intra-OVLT injection of SNAP. 5. The PGE2-induced fever was potentiated, rather then attenuated, by pretreatment with an intra-OVLT dose of animoguanidine (1000 micrograms), L-NMMA (100 micrograms) or L-NIO (200 micrograms). 6. These results suggest that iNOS-COX pathways in the OVLT represent an important mechanism for modulation of pyrogenic fever in rabbits.

Topics: Animals; Body Temperature Regulation; Cyclic GMP; Cyclooxygenase Inhibitors; Dinoprostone; Enzyme Inhibitors; Fever; Guanylate Cyclase; Hypothalamus; Indomethacin; Lipopolysaccharides; Male; Nitric Oxide; Nitric Oxide Synthase; Prostaglandin-Endoperoxide Synthases; Rabbits

Activity of the stress protein, heme oxygenase-1 (hsp32; HO-1), produces carbon monoxide (CO), the potential messenger molecule for excitatory N-methyl-D-aspartate receptor-mediated events, in the hippocampus. Long-term stress caused by elevated adrenocorticoids induces pathological changes in CA1-CA3 neurons of the hippocampus; the adrenal hormones also exacerbate damage from stress. In rats chronically treated with corticosterone, we examined expression of HO-1 and its response to thermal stress in the hippocampus. An unprecedented appearance of scattered immunoreactive astrocytes marked the molecular layer of the hippocampus in corticosterone-treated rats. Steroid treatment showed no discernible effect on whole-brain HO-1 mRNA. When these rats were subjected to hyperthermia, neurons in the CA1-CA3 area, including pyramidal cells, exhibited intense immunoreactivity for the oxygenase and a pronounced increase (approximately 10-fold) in number. HO-1 is essentially undetectable in this area when rats are exposed to chronic corticosterone alone or thermal stress by itself, or in control rats. In contrast, similar analysis of hilar neurons showed no apparent effect on either the number or relative intensity of HO-1-immunostained cells after treatment. Corticosterone treatment also intensified the stress response of cerebellum, including Purkinje cells and Bergmann glia in the molecular layer. In brain, despite a pronounced reduction in NO synthase activity in corticosterone-treated and/or heat-stressed animals, the level of cyclic GMP was not significantly reduced. These observations are consistent with the hypothesis that responsiveness to environmental stress of CA1-CA3 neurons brought about by chronic elevation in circulating adrenocorticoids results in an increased excitatory neuronal activity and eventual hippocampal degeneration. Moreover, these findings yield further support for a role of CO in the production of cyclic GMP in the brain.

Topics: Amino Acid Oxidoreductases; Animals; Cerebellum; Corticosterone; Cyclic GMP; Fever; Glucocorticoids; Heme Oxygenase (Decyclizing); Hippocampus; Hot Temperature; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Neurons; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Physiological

There is much debate on the mechanism by which blood-borne pyrogens trigger prostaglandin E2 (PGE2) synthesis in brain and fever. This investigation was undertaken to determine whether nitric oxide qualifies as a signal transducer for pyrogens at the interface between blood and brain. Experiments were carried out in vitro and in vivo using, respectively, preparations of cerebral tissue and microvessels from the rat, and the conscious, chronically instrumented cat. In vitro preparations produced PGE2 and its production increased during a 30-min treatment with interleukin 1 (brain tissue) or endotoxin (microvessels). In addition, both pyrogens increased cyclic GMP levels in cerebral microvessels. In both brain tissue and microvessels, NG-nitro-L-arginine had no effect on basal PGE2 release, while it curtailed the pyrogen-stimulated release. The same treatment reduced the cyclic GMP accumulation brought about by pyrogens in the microvessels. Conversely, in the conscious cat, inhibitors of nitric oxide synthesis (NG-monomethyl-L-arginine, NG-nitro-L-arginine) had no effect on fever and the concomitant elevation of PGE2 in cerebrospinal fluid, regardless of the pyrogen used (endotoxin, interleukin 1) and the route of administration (intravenous, intracerebroventricular). We conclude that nitric oxide may serve as a pyrogen mediator in brain. This mediator function, however, is seemingly not important in the development of fever.

Topics: Animals; Cats; Cyclic GMP; Dinoprostone; Endotoxins; Female; Fever; In Vitro Techniques; Interleukins; Male; Nitric Oxide; Pyrogens; Rats; Recombinant Proteins

Presently we have investigated the carbon monoxide generating capacity of the cardiovascular system under normal and stress conditions by examining the microsomal heme oxygenase system at the transcript, protein and activity levels; and have assessed response of heart nitric oxide (NO) synthase activity and cyclic GMP levels to stress. Heme oxygenase (HO) isozymes, HO-1 (HSP32) and HO-2, catalyze the rate limiting step in the only known pathway in eukaryotes for the generation of the potential cellular message, carbon monoxide, and the antioxidant, bilirubin. We show expression of HO-1 and HO-2 at both the transcription and protein levels under normal conditions in the heart and descending aorta, and demonstrate the sensitivity of only the HO-1 isozyme to heat stress in these tissues. The ratio of the two HO-2 homologous transcripts (approximately 1.9 and 1.3 Kb) present in the atrium, ventricles and descending aorta and their levels were not altered by hyperthermia (42 degrees C, 20 min) when measured 1 or 6 hr after treatment. In contrast, hyperthermia caused a rapid, robust and coordinate increase of approximately 10- to 32-fold in the approximately 1.8-Kb HO-1 mRNA in these tissues when measured 1-hr post-treatment. Hyperthermia also caused a significant increase in both HO-1 protein and heme degradation capacity in the heart. Furthermore, the induction of HO-1 protein in the heart was accompanied by a significant elevation in tissue cyclic GMP level first detected 1-hr post-treatment and was sustained 6 hr after heat shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Animals; Cyclic GMP; Enzyme Induction; Fever; Heat-Shock Proteins; Heme Oxygenase (Decyclizing); Isoenzymes; Male; Myocardium; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; RNA, Messenger

Qingwen Baidu Yin (QBY) has good curative effects on the endotoxic fever of rabbits induced by injecting endotoxin of E. Coli. The test group was given QBY orally, while the control group was given NS orally instead. Result showed QBY could: (1) Markedly inhibit the fever, it was effective in reducing febrile curve. delta T and TRI5 of the test group were smaller (P < 0.001). (2) Ameliorate the leukocytopenia and leukocytosis, and improve thrombocytopenia. (3) Antagonize hyperviscosity syndrome and had the actions of depolymerization and dilution. (4) In test group, the increased cAMP content in plasma was reduced, and the decreased cGMP content raised, the ratio of cAMP and cGMP was nearly normal. All these provided the clue in elucidating the essence of "Excessive Yang causes Heat" and "Predominance of Yang leads to disorder of Yin". (5) Pathomorphological examination showed that QBY had the functions of protecting the internal organs and reducing the organic damage induced by endotoxing in rabbits.

Topics: Animals; Blood Cell Count; Blood Viscosity; Cyclic AMP; Cyclic GMP; Drugs, Chinese Herbal; Endotoxins; Escherichia coli; Female; Fever; Male; Rabbits; Yin Deficiency

Recently, there has been a variety of reports of adverse drug reactions during therapy with the flavonoid Cianidanol (Ci), a cytoprotective radical scavenger, especially involving haemolytic anaemia and drug fever. To elucidate whether the fever was due to a direct, antigen-independent interaction of Ci with immune competent cells, its effect on macrophage (M phi) function and early biochemical events during lymphocyte activation has been examined. A direct interaction of Ci with M phi was demonstrated, resulting in increased secretion of interleukin-1 (IL-1). The influence of Ci on lymphocyte activation was assessed by measuring levels of cyclic AMP and GMP. At high concentrations of Ci, cAMP levels were increased, and at low Ci concentrations cGMP levels were elevated. Both findings are correlated with lymphocyte proliferation and function, which is increased at low and decreased at high concentrations of Ci. The synthesis of prostaglandin E2 by M phi, an important factor in M phi-mediated suppression, was reduced by increasing doses of Ci, which inhibited M phi-cyclooxygenase. Ci did not affect phospholipase A2 activity. These findings indicate that flavonoid-induced fever may be due to allergic as well as pseudo-allergic mechanisms, the latter probably caused by increased antigen-independent release of IL-1, the endogenous mediator of fever.

Topics: Catechin; Cyclic AMP; Cyclic GMP; Dinoprostone; Fever; Humans; Indomethacin; Interleukin-1; Macrophages; Mitogens; Phospholipases A; Phospholipases A2; Phytohemagglutinins; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Radioimmunoassay

Topics: Adipose Tissue; Animals; Blood Glucose; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Experimental; Fever; Male; Rats; Rats, Inbred Strains

Topics: Animals; Body Temperature; Body Temperature Regulation; Cats; Cyclic GMP; Dibutyryl Cyclic GMP; Fever; Hypothermia; Injections, Intraventricular; Time Factors