icatibant and Fever

1. The effect of central injection of selective kinin B1 and B2 receptor antagonists on the febrile response induced by endotoxin (E. coli lipopolysaccharide, LPS) in rats was investigated. 2. Intracerebroventricular (i.c.v.) injection of a selective B2 receptor antagonist (Hoe-140, 8 nmol) reduced the early (0-2 h), but increased the late phase (4-6 h) of the febrile response induced by intravenous (i.v.) injection of LPS (0.5 microgram kg-1). 3. Co-administration of Hoe-140 (8 nmol, i.c.v.) with LPS (0.5 microgram kg-1, i.v.), followed 2.5 h later by the i.c.v. injection of a selective B1 receptor antagonist [des-Arg9-Leu8]-bradykinin (BK, 8 nmol), significantly reduced the febrile response induced by LPS throughout the whole experimental period. 4. Intravenous injection of Hoe-140 (1 mg kg-1) significantly reduced the febrile response induced by LPS (0.5 microgram kg-1, i.p.). 5. Pretreatment (24 h) with LPS (0.5 microgram kg-1, i.v.) reduced the febrile response induced by BK or [Tyr8]-BK (both, 5 nmol, i.c.v.), but markedly increased the febrile response induced by [des-Arg9]-BK (5 nmol, i.c.v.). The response induced by [des-Arg9]-BK in LPS-pretreated rats was significantly inhibited by co-injection of [des-Arg9-Leu8]-BK (15 nmol, i.c.v.). 6. The results suggest that kinins are involved in the induction of LPS-induced fever and that central B2 and B1 receptors are activated during the initial and late phase of this response, respectively. The results also suggest that downregulation and/or desensitization of B2 receptors and induction and/or upregulation of B1 receptors in LPS-pretreated animals may have a significant pathophysiological role in the induction and maintenance of fever. These observations may be specifically important in the case of chronic inflammatory conditions, because the BK metabolite [des-Arg9]-BK, so far considered an inactive metabolite, acquires an active and relevant role with the progressive expression of B1 receptors that occurs in such states.

Topics: Animals; Bradykinin; Central Nervous System; Endotoxins; Fever; Lipopolysaccharides; Male; Rats; Rats, Wistar; Receptors, Bradykinin

1. Mechanisms involved in the plasma extravasation observed following thermal injury of rat dorsal skin were investigated. 2. Heat applied to the dorsal skin of anaesthetized rats by a temperature-controlled skin heater (1 cm diameter) for 5 min induced temperature-dependent plasma protein extravasation at 48-48.5 degrees C, measured for up to 4 h following initiation of heat. 3. A tachykinin NK1 receptor antagonist (SR140333), a bradykinin B2 receptor antagonist (HOE 140) and a cyclo-oxygenase inhibitor (indomethacin), when given as cotreatments prior to the selected measurement period, markedly suppressed oedema formation observed over 0-1 h (P < 0.05) but not that observed over 3-4 h after injury. 4. These results indicate that although neurokinins, bradykinin and cyclo-oxygenase products may be important for the early response to thermal injury, they do not appear to play an important role in the ongoing oedema response. 5. Neutrophils accumulate at the inflammatory site by 4 h after thermal injury. Therefore, the effect of depletion of circulating neutrophils by a rat anti-neutrophil antiserum on oedema formation over the 0-4 h period was investigated. The results show that oedema formation was similar in control and anti-neutrophil-treated rats. 6. In conclusion, the data from the present study indicate that neuropeptides as well as other vasoactive mediators play a role in the acute plasma extravasation observed after thermal injury, but not in the ongoing inflammatory injury. Neutrophils, despite their presence at sites of thermal injury, do not appear to be involved in mediating the oedema formation observed up to 4 h after thermal injury.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin Receptor Antagonists; Edema; Fever; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptor, Bradykinin B2; Tachykinins

1. E. coli lipopolysaccharide (LPS) produced a dose-dependent (dose range: 0.02-150 micrograms) increase in rat core temperature that was maximal 6 h after intracerebroventricular (i.c.v.) administration. LPS (200 ng) increased core temperature by 1.0 +/- 0.2 degrees C, 6 h following administration, as compared to vehicle-treated controls (-0.2 +/- 0.2 degrees C). 2. LPS-induced (200 ng) hyperthermia was prevented by co-administration of the bradykinin (BK) B2 receptor antagonist, Hoe 140 (10 and 30 pmol, i.c.v.) or by indomethacin (10 nmol, i.c.v.). 3. Systemic administration of Hoe 140 at doses up to 1 mumol kg-1, s.c., did not attenuate LPS-induced (200 ng, i.c.v.) hyperthermia. However, LPS hyperthermia was significantly reduced by systemic administration of indomethacin (1 mumol kg-1, i.v.). 4. Co-administration of the selective B1 receptor antagonists, [des-Arg9, Leu8]BK (0.1 - 1 nmol, i.c.v.) or [des-Arg10] Hoe 140 (0.1 - 1 nmol, i.c.v.), did not prevent LPS-induced hyperthermia. 5. It is concluded that the development of hyperthermia following central administration of endotoxin requires activation of central, but not peripheral bradykinin B2 receptors. The formation of kinins within the CNS may be an important initial component of CNS inflammation following infection.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Fever; Indomethacin; Injections, Intraventricular; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2

The present study investigated the development of hyperthermia and thermal and mechanical hyperalgesia following i.c.v. injections of E. coli lipopolysaccharide (LPS) in rats. LPS increased core temperature and this was prevented by i.c.v. administration of HOE 140, a kinin B2 receptor antagonist or by indomethacin i.c.v. or i.v. B1 receptor antagonists had no effect. LPS induced thermal and mechanical hyperalgesia which was reversed by i.c.v. HOE 140 and indomethacin i.c.v. and i.v., but not by B1 receptor antagonists. These results indicate that injections of endotoxin to the CNS induces hyperthermia and hyperalgesia and that kinins, acting on centrally located B2 receptors, and prostanoids are involved.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Fever; Hyperalgesia; Indomethacin; Inflammation; Injections, Intraventricular; Kinins; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2