The Effect of Central Injection of Angiotensin-Converting Enzyme Inhibitor and the Angiotensin Type 1 Receptor Antagonist on the Induction by Lipopolysaccharide of Fever and Brain Interleukin-1 Response in Rats

We recently reported an involvement of peripheral angiotensin II (ANG II) in the development of both the fever and the peripheral interleukin (IL)-1 production induced in rats by a systemic injection of lipopolysaccharide (LPS). The present study was performed to investigate whether brain ANG II contributes to the fever and IL-1 production in the rat brain induced by i.c.v. injection of LPS. LPS (0.2 and 2 g i.c.v.) induced dose-related fevers and increases in the brain (hypothalamus, hippocampus, and cerebellum) concentrations of IL-1 . These effects were significantly inhibited by i.c.v. administration of either an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin type 1 (AT1) receptor antagonist. By contrast, the ACE inhibitor had no effect on the IL-1 (i.c.v.)-induced fever, whereas the AT1 receptor antagonist enhanced (rather than reduced) it. The AT1 receptor antagonist had no effect on the brain levels of prostaglandin E2 in rats given an i.c.v. injection of IL-1 . These results suggest that in rats, brain ANG II and AT1 receptors are involved in the LPS-induced production of brain IL-1 , thus contributing to the fever induced by the presence of LPS within the brain. Angiotensin II (ANG II), a bioactive peptide well known to play an important role in blood pressure and body fluid regulation, seems to participate in inflammatory responses, too. For example, an angiotensin-convertingenzyme (ACE) inhibitor has been shown to have an antiinflammatory effect (Godsel et al., 2003). Furthermore, ANG II and ANG II type 1 (AT1) receptors are involved in cardiovascular inflammation, such as monocyte infiltration (Usui et al., 2000). Recently, we reported results suggesting that ANG II is involved in the development of the fever (an inflammation-related response) induced by i.v. injection of lipopolysaccharide (LPS, 2 g/kg) in euhydrated rats as well as in dehydrated rats (in which the secretion of ANG II is elevated) (Watanabe et al., 2000). In fact, the LPS-induced fever seen in that study was significantly attenuated by an ACE inhibitor, injected i.v. Because, as the first step in fever induction the pyrogenic/ proinflammatory cytokine interleukin (IL)-1 is released from macrophages after their stimulation by LPS (Kluger, 1991; Dinarello, 1999), we speculated that ANG II might contribute to the LPS-induced peripheral production of IL-1. Indeed, i.v. injection of LPS increases the liver concentration of IL-1 in dehydrated rats, and this effect can be significantly attenuated by an ACE inhibitor or by an AT1 receptor antagonist, in each case given i.v. (Miyoshi et al., 2003). However, we found that an i.v. injection of LPS (2 g/kg) did not induce any detectable changes in the brain level of IL-1 (our unpublished observations). It seemed likely from these results that peripheral ANG II is involved in the development of the peripheral production of IL-1 (induced by LPS). The brain has its own renin-angiotensin system and its own AT1 receptors that play important roles in blood pressure and body fluid regulation (Tsutsumi and Saavedra, 1991; Rowe et al., 1992; Wright and Harding, 1992), alongside the regulation mediated via peripheral ANG II. On the other hand, an i.c.v. injection of LPS reportedly leads to Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.103.060392. ABBREVIATIONS: ANG II, angiotensin II; ACE, angiotensin-converting-enzyme; AT1 receptor, angiotensin type 1 receptor; LPS, lipopolysaccharide; IL, interleukin; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; PG, prostaglandin; ANOVA, analysis of variance; NFB, nuclear factorB. 0022-3565/04/3083-865–873$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 308, No. 3 Copyright © 2004 by The American Society for Pharmacology and Experimental Therapeutics 60392/1125600 JPET 308:865–873, 2004 Printed in U.S.A. 865 at A PE T Jornals on N ovem er 9, 2017 jpet.asjournals.org D ow nladed from marked fever and IL-1 production in the brain (De Simoni et al.,1997; Tsushima and Mori, 2000). The i.c.v. injection of LPS provides a model of bacterial meningitis, in which bacteria (or LPS) enter the brain and induce pathological changes such as fever and cerebral inflammation (Korytko and Boje, 1996; Tsushima and Mori, 2000). However, it is at present, unknown whether brain ANG II contributes to the production of IL-1 within the brain, just as peripheral ANG II probably promotes the peripheral production of IL-1 (see above). In this study, we investigated the effects of an i.c.v. injection of an ACE inhibitor or an AT1 receptor antagonist on the fever and the brain IL-1 response induced in rats by i.c.v. LPS. We also examined the effect of i.c.v. treatment with an ACE inhibitor or an AT1 receptor antagonist on the fever due to i.c.v. injection of IL-1 . Materials and Methods