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1 Pharmaceutical Division, CNS Preclinical Research, F. Hoffmann-LaRoche, CH-4070 Basel, Switzerland; and 2 Division of Infectious Diseases, University of Colorado Health Science Center, Denver, Colorado 80262
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We have studied, using a telemetry system,
the pyrogenic properties of recombinant murine interleukin-18 (rmIL-18)
injected into the peritoneum of C57BL/6 mice. The effect of IL-18 was
compared with the febrile response induced by human IL-1
,
lipopolysaccharide (LPS), and recombinant murine interferon-
(rmIFN-). Both IL-1 and LPS induced a febrile response within the
first hour after the intraperitoneal injection, whereas rmIL-18
(10-200 µg/kg) and rmIFN- (10-150 µg/kg) did not cause
significant changes in the core body temperature of mice. Surprisingly,
increasing doses of IL-18, injected intraperitoneally 30 min before
IL-1, significantly reduced the IL-1-induced fever response. In
contrast, the same pretreatment with IL-18 did not modify the febrile
response induced by LPS. IFN- does not seem to play a role in the
IL-18-mediated attenuation of IL-1-induced fever. In fact, there was
no elevation of IFN- in the serum of mice treated with IL-18, and a
pretreatment with IFN- did not modify the fever response induced by
IL-1. We conclude that IL-18 is not pyrogenic when injected
intraperitoneally in C57BL/6 mice. Furthermore, a pretreatment with
IL-18, 30 min before IL-1, attenuates the febrile response induced
by IL-1.
interleukin-1; interferon-
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INTERLEUKIN-18
(IL-18), initially characterized as interferon- (IFN-)-inducing
factor, is mainly produced by activated macrophages and participates in
the T helper cell type 1 (Th1) response during immunorecognition (33). IL-18 acts as a cofactor, inducing
the production of IFN- usually in the presence of another stimulus [for instance, lipopolysaccharide (LPS) or IL-12], and potentiates Th1- and natural killer cell-induced cytotoxicity by increasing the expression of Fas ligand (6, 33).
The proinflammatory role of IL-18 has been extensively characterized in
vitro, showing that IL-18 promotes the innate immune response, mainly
inducing the production of tumor necrosis factor (TNF)-
,
IL-1/, IL-6, IL-8, macrophage inflammatory protein-1, and
monocyte-chemoattractant protein-1 (12, 29, 34,
37) with no direct effect on the production of
prostaglandins (PGs; Ref. 38). In vitro studies have also
confirmed that mature IL-18 is produced by various cell types in
response to endotoxins (LPS), and in vivo studies showed that IL-18
could be partially responsible for the LPS-induced lethality in mice
(20, 39). During sepsis, circulating IL-18 levels are
increased in humans (16).
The similarities between IL-18 and IL-1/, both in structural and
in functional terms, have been highlighted by several studies. Both
IL-1 and IL-18 gene expression are induced by LPS. However, differently
from all other proinflammatory cytokines, 1) IL-18 gene
expression is constitutively high, 2) IL-18 mRNA and IL-18 precursor protein (24 kDa) are broadly expressed in several tissues and
cell types (4, 25, 30, 35, 36), and 3) IL-18
actions may be regulated by changes in concentration of IL-18 binding protein. Neuroendocrine cells in adrenal glands and pancreas
(21) also express pro-IL-18 mRNA, possibly in response to
stress events. By RT-PCR it was possible to demonstrate the
constitutive expression of the mature transcript coding for IL-18
precursor in rat brain (42), probably mainly in astrocytes
and microglia (4).
Similarly to IL-1 precursor, the pro-IL-18 is cleaved to the mature
active form mainly by IL-1-converting enzyme, and in the case of
IL-18 the enzymatic cleavage is probably the main mechanism of control
on the production of bioactive IL-18 (11, 14).
The cellular effects of IL-18 are a consequence of the specific
interaction with the membrane-bound IL-18 receptor (IL-18R) complex
(IL-18R/). Signal transduction by IL-18 is highly analogous to
that observed in the case of IL-1R type I (IL-1RI) (33). After binding to the IL-18R chain (24), IL-18/IL-18R
complex recruits the IL-18 accessory protein (IL-18R) (5,
23). This increases the affinity of the ligand for the receptor
complex, and a signal is transduced. A soluble IL-18-binding protein
binds and neutralizes IL-18 effects, reducing the amount of cytokine available for the interaction with IL-18R complex (38). In
the periphery the distribution of IL-18R is rather broad, and
IL-18R mRNA can be detected mainly in lymphocytes and hematopoietic
cells (32).
The intracellular, postsignal cascade of IL-18R kinases is nearly
identical to that of IL-1RI. 1) IL-1RI and IL-18R signaling involves the recruitment of MyD88 and the activation of a common kinase, IL-1 receptor-associated kinase (IRAK; Refs. 17,
22). 2) Another kinase, known as TNF receptor
(TNFR)-activating factor-6 (TRAF-6), contributes to the signal
transduction system of both IL-1 and IL-18 receptors (27)
and results in activation of nuclear factor (NF)-
B (26,
41). NF-B translocation to the nucleus is associated with
initiation of cyclooxygenase-2 (COX-2) gene expression.
The observed functional similarities between IL-18 and IL-1/
suggest the presence of partially overlapping roles for these cytokines
in the control of the acute phase response during infection. This is
also suggested by the recent study of Kubota et al. (28), showing that IL-18 promotes sleep in rabbits and rats.
Considering that IL-1 is the main endogenous pyrogen and that
IL-1-induced fever is mediated by intrahypothalamic production of
PGE2 (8), we studied the pyrogenic properties
of IL-18 and compared the effect of IL-18 with the febrile response
triggered by IL-1 and LPS, respectively.
IL-18 is not inducing PGE2 production in peripheral cells;
this observation, however, is not per se predictive of a lack of pyrogenicity of this proinflammatory cytokine. IL-6, an endogenous pyrogen in humans and rabbits, does not induce COX-2 expression and PG
production in monocytes or synovial fibroblasts. Moreover, IFN-,
which is also pyrogenic in humans, suppresses LPS- and IL-1-induced PG
production in monocytes. Therefore, to resolve this issue, we have
tested the pyrogenicity of recombinant murine IL-18 in mice.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Mice. C57BL/6J male mice (25-30 g, Biological Research Laboratories, Füllinsdorf) were used for this study. They were individually housed with free access to food and water at vivarium temperature of 25°C (30-40% humidity) for 7-10 days before the surgery (light from 7 AM to 7 PM). The animals were acclimated at 29.5°C after the surgery. All animals were kept on the same standard diet, Kliba no. 243 (12.6 MJ/kg).
Treatments.
LPS was from Escherichia coli (serotype 026:B6, Sigma lot
107H4091, cell culture tested). Recombinant human (rh) IL-1 was from
R&D Systems (Minneapolis, MN; helper T cells proliferation assays:
ED50 = 5-10 pg/ml). Recombinant murine (rm)
IFN- was from R&D Systems (antiviral test in L929;
ED50 = 0.1-0.4 ng/ml). rmIL-18 was expressed and
purified by Peprotech (Rocky Hill, NJ) (23). rmIL-12 was a
kind gift of Genetics Institute (Andover, MA); the specific activity of
IL-12 was 2.7 × 106 U/mg. LPS and cytokines were
reconstituted in pyrogen-free saline solution. Aliquots were stored at
20°C, and each frozen aliquot was used only once. LPS or cytokines
were injected intraperitoneally in pyrogen-free saline solution.
Control mice were injected with pyrogen-free saline solution. All
treatments were carried out between 9 AM and 11 AM. The volume of
injection was calculated in proportion to the body weight, and it
ranged between 0.1 and 0.2 ml. The total volume of liquids injected
into the peritoneum, during multiple treatments, never exceeded 0.4 ml.
Implant of telemetry probes. Telemetry probes (Vitalview 4000, MiniMitter, Sunriver, OR) were inserted into the mouse peritoneum under systemic anesthesia with diazepam (5 mg/kg ip) and ketamine (100 mg/kg ip). For the postoperative analgesic treatment, buprenorphine (0.05 mg/kg sc) was used twice a day for 1 day after the surgery. Animals were then acclimated for 5-7 days at 29.5 ± 0.5°C of ambient temperature (30-40% humidity) before any further treatment.
Measurement of core body temperature in mice. Core body temperature and horizontal motor activity values were recorded every minute in freely moving animals housed in single cages, starting from the evening before the day of the experiment and until 18 h after the injections. This study received the approval of the Cantonal Veterinary office of the city of Basel, Switzerland.
Measurement of IFN- levels in the serum of mice treated with
IL-18.
Mice (8 wk old) were treated for 4 days with IL-18 or murine IL-12 (400 ng/mouse ip). The serum was taken from the retroorbital plexus 2 h
after the last injection. IFN- levels were measured with an
enzyme-linked immunosorbent assay kit from Endogen (Wobur, MA).
Statistical analysis. Core body temperature was recorded every minute, and data were averaged every 10 min. The results were analyzed using ANOVA followed by post hoc tests (UNISTAT software package).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of IL-18, IL-1, and LPS on core body temperature of
C57BL/6 mice.
IL-1 (10 µg/kg ip) causes fever in mice acclimated in
thermoneutral environment (29.5 ± 0.5°C) (Fig.
1A). During the fever response, the core body temperature increases about 1-1.5°C,
with a maximal rise within 2 h after the intraperitoneal
injection. The core body temperature of mice injected with IL-1 is
different from that of saline-injected animals for ~6 h after the
treatment. The core body temperature of treated mice was not
significantly different from that of mice injected with saline solution
~24 h after the treatment (data not shown).
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and LPS were chosen as
the minimal doses causing a reproducible febrile response in this
strain of mice (data not shown).
Animals consistently exhibited a similar stress reaction immediately
after the intraperitoneal injection, with a sudden hyperthermia lasting
~45 min after the injection (Fig. 1). This reaction was longer (~60
min) in the case of animals injected twice (Fig.
2).
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(10-150 µg/kg) (Fig. 1, B and
C, respectively) induced a sustained increase of the core
body temperature within 5-6 h after the treatment. No changes in
the circadian rhythm of the core body temperature were observed during
the 24 h after the treatment (data not shown).
No signs of sickness or changes in horizontal locomotor activity were
observed in mice treated with IL-18.
The doses of rmIL-18 used in this study (10-50 µg/kg;
0.25-1.25 µg/mouse) are in the range of IL-18 doses active in
suppressing the growth of MetA tumor cell ascites and increasing
histidine decarboxylase activity in mouse tissues (31,
43).
At a dose of 200 µg/kg ip of IL-18, no sustained effect on core body
temperature was observed (data not shown).
Effect of a pretreatment with IL-18 or IFN- on IL-1- and
LPS-induced fever.
As described above, mice pretreated (30 min) with IL-18 (10-200
µg/kg ip) developed a reduced febrile response to IL-1 (10 µg/kg
ip) (Fig. 2). This reduction in IL-1-induced fever by IL-18 was dose
dependent. In fact, the pretreatment with IL-18 at 10 µg/kg resulted
in a slight reduction of IL-1-induced fever, whereas the injection
of 50 µg/kg of IL-18 30 min before IL-1 resulted in a significant
shortening of the febrile period in each of the IL-18-treated animals.
The highest IL-18 dose tested in this study, 200 µg/kg, completely
blocked IL-1-induced fever response. In contrast, similar
attenuation of LPS-induced fever (50 µg/kg) was not observed with a
pretreatment by IL-18 (50 µg/kg) (Fig. 3). Thus, in our experimental conditions,
the suppression of fever by pretreatment with IL-18 (50 µg/kg ip)
appears to be effective for IL-1 and not for LPS.
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fever in mice. In fact, mice pretreated
with the highest dose of IL-18 used in this study (200 µg/kg) mounted
a normal IL-1-induced febrile response when IL-18 was injected
1 h before IL-1 (Fig. 4) compared
with 30-min pretreatment (Fig. 2).
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, particularly with IL-12 or
other T-cell activators, we examined the possible effect of IFN- on
IL-1-induced fever. A pretreatment (30 min) with IFN- (50 µg/kg
ip) did not reduce IL-1-induced fever under these experimental
conditions (Fig. 5).
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Serum levels of IFN-.
IFN- was increased slightly in the circulation of mice injected each
day, for 4 days, with IL-18 (16 µg/kg ip). However, the serum levels
were not statistically different from those observed in control mice
injected with saline (Table 1). In
contrast, mice injected with IL-12 exhibited high levels of IFN-.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Fever is a stereotypic response to endogenous and exogenous
pyrogens, associated with increased serum levels of proinflammatory cytokines (IL-1/, TNF-, and IL-6) and hypothalamic production of PGs (mainly PGE2), that trigger fever interacting with
EP3 receptors (13). Exogenous pyrogens, like LPS, trigger
fever via the interaction with Toll-like receptors (TLR) expressed in macrophagic cells, endothelial cells, or perivascular cells of the
organum vasculosum lamina terminalis, with either direct release of
PGE2 or the subsequent release of endogenous pyrogens
(i.e., cytokines) (13).
In the case of intraperitoneal injection of IL-1 (10 µg/kg) into
mice, the febrile response is only partially due to the circulating
proinflammatory cytokine (18). In fact, the effect of the
intraperitoneal injection of IL-1 is amplified by the local
production of IL-1/, TNF-, and IL-6 by peritoneal macrophages, and fever is also triggered via the activation of the sensory afferent
part of the vagal nerve. In rats a surgical cut of the sensory part of
this nerve in the subdiaphragmatic region completely prevents the
development of IL-1-induced fever after intraperitoneal injection of
IL-1 (19). Moreover, the synthesis of IL-1 can be
detected in the vagal nerve and in the nodose ganglion soon after the
intraperitoneal injection of LPS (15). Therefore, we
hypothesized that intraperitoneal injection of IL-18 would also cause
fever by similar mechanisms. However, intraperitoneal injection of
IL-18 did not produce fever.
Endogenous or exogenous pyrogens can cause fever in all endotherms, because they trigger the shift upward of the hypothalamic core temperature set point, with a subsequent increase in metabolic rate and facultative thermogenesis. In the case of small rodents like mice and rats, it is necessary to acclimate the animals in thermoneutral conditions (29-30°C of ambient temperature for mice) before the treatment, to allow them to mount a proper febrile response (16).
C57BL/6 mice are an inbred strain commonly used for studies of in vivo
effects of cytokines and of T-cell-mediated immune responses associated
with the production of IFN- (1, 3).
In the experimental conditions used in the present study both IL-1
(10 µg/kg ip) and LPS (50 µg/kg ip) cause a prolonged fever
response in C57BL/6 mice. LPS- and IL-1-induced fevers in mice are
very similar both in terms of time course and of magnitude of the
effect (data not shown) despite the fact that LPS fever was sustained
in our experimental conditions by the induction of several endogenous
pyrogens (TNF-, for instance). In fact, LPS-induced fever is still
present in IL-1/ knockout. Moreover, LPS-induced fever,
in rabbits and in humans, is not affected by the coinfusion of IL-1
receptor antagonist (IL-1ra; Ref. 13).
Human IFN- causes fever when injected subcutaneously in humans or
intraperitoneally in rabbits. In mice, however, rmIFN- does not
cause fever when injected in doses ranging from 10 to 150 µg/kg ip
(2).
In the same experimental model, murine IL-18 (10-200 µg/kg ip) does not cause a significant and sustained increase of the core body temperature (Fig. 1). These results confirmed our earlier unpublished observations using human IL-18 in mice.
Recently, Reznikov et al. (38) reported a significant
biological difference between the two proinflammatory cytokines:
IL-1 and IL-18. In vitro, IL-18 does not trigger
PGE2 production in human peripheral blood mononuclear cells
and, when coincubated with IL-1, even causes a marked reduction of
PGE2 production (IFN- mediated). Therefore, in vivo
studies are required to understand if IL-18 is not causing fever
because of a lack of production of PGE2 in the
hypothalamus. However, the evidence that IL-18 is not pyrogenic when
injected intraperitoneally in mice suggests a main difference in the
neurological effects of IL-1 and IL-18.
Experimental antipyretic strategies usually block the effect of
endogenous pyrogens (IL-1, IL-6, and TNF-) via the inhibition of
PGE2 formation by inhibiting COX enzymes (COX-1 and/or
COX-2). In each case, the antipyretic agent is injected 30 min before the pyrogen. Using a classical protocol for the study of antipyretic agents, we show in the present study that IL-18 reduces the fever response induced by rhIL-1 but not LPS in a dose-dependent manner.
It is unlikely that IFN- is responsible for the observed effect of
IL-18 on IL-1 fever. In fact, rmIL-18 (16 µg/kg) injected intraperitoneally in mice for 4 days does not increase IFN- levels in the serum, and, more importantly, a pretreatment with IFN- (50 µg/kg ip) does not modify IL-1-induced fever (Fig. 5).
A central production of IFN- at the level of periventricular organ
or hypothalamus could, however, play a role in the control of the
pyrogenic response induced by IL-1. Similarly to what was observed
by Reznikov et al. (38) in blood mononuclear cells, central IL-1-induced PG production could be reduced by a cotreatment with IL-18 because of the local induction of IFN-.
Several peripheral or central events could as well account, at least
partially, for the observed pharmacological IL-18 antagonism on
IL-1-induced fever. IL-18 could, for instance, act on endogenous antipyretic/anti-inflammatory mechanisms such as IL-4 secretion, the
epoxygenase pathway, or the central release of arginine vasopressin or
IL-1ra, for instance (13).
However, the lack of effect of IL-18 pretreatment on LPS-induced fever
suggests the presence of cellular events specific for IL-1RI-mediated
signal transduction. The observed attenuation of IL-1 fever could
be, for instance, the result of mechanisms of sequestration at the
receptor accessory protein level or at the level of intracellular
signaling proteins, like MyD88 or IRAK. In vitro studies are necessary
to further address this hypothesis. However, when considering this
hypothesis, we should remember that LPS also mobilizes IRAK1/2-TRAF6.
Thus possible functional interactions between IL-18 and IL-1 receptor
signaling must be upstream from IRAK1/2-TRAF6 in the TLR-signaling pathway.
The effect of IL-18 on IL-1 fever is dependent on the time protocol
of the pretreatment. IL-18 (200 µg/kg) is able to inhibit completely
IL-1-induced fever when injected 30 min before IL-1 (Fig. 2),
whereas the effect is no longer present if the same dose of IL-18 is
injected 1 h before IL-1 (Fig. 4).
It is rather difficult to explain the time dependence of the antipyretic effect of the IL-18 pretreatment with the present, rather scanty, knowledge of in vivo IL-18 effects. Our experimental observation could be consistent with the hypothesis of cross-talk between fast intracellular events associated with the activation of IL-1R and/or IL-18 receptor complexes.
A similar time-dependent effect could be observed while studying the
antipyretic effect of IL-1ra pretreatment: in this case, the blockade
of IL-1 receptors with IL-1ra is effective on IL-1-induced fever
response when IL-1ra is injected 15 min before IL-1 (7, 13) or after IL-1 because of the short plasma half-life of IL-1ra. Pharmacokinetic reasons cannot be ruled out also in the case of
the observed time dependence of the IL-18 effect.
Moreover, because of the tight time dependence of the IL-18 effect on
IL-1, we cannot rule out completely that the observed lack of effect
of IL-18 on LPS-induced fever is due to the protocol of treatment we
used. We are further exploring this possibility.
This is the first study addressing the effect of a systemic treatment with IL-18 on core body temperature. We conclude that IL-18 is not causing fever per se when injected intraperitoneally in C57BL/6 mice. These results are in agreement with the in vitro observation that IL-18 is not able to trigger the production of PGE2 in macrophage-like cells (38) and with the study of Kubota et al. (28) showing no changes in brain temperature in rats treated with intraperitoneal IL-18. Moreover, a recent study carried out by Stuyt RJL, Netea MG, Kullberg BJ, and van der Meer JWM, (unpublished data) has further confirmed that recombinant human IL-18 (1 µg/kg iv) is not pyrogenic in rabbits.
IL-18 (10-200 µg/kg ip) exhibits an in vivo effect when tested
in a protocol of pretreatment on IL-1-induced fever. In fact, we
could observe a significant reduction of IL-1-induced fever when
IL-18 is injected 30 min before the pyrogen. Considering that this
effect is specific for IL-1-induced fever and that it is not
observed when IL-18 is injected 1 h before IL-1, we suggest the presence of cross-talk at the level of early IL-1R-mediated intracellular events.
Perspectives
New ligands belonging to the structural IL-1 family have been recently discovered together with a large series of TLR receptors. All the known ligands of the IL-1R structural superfamily exhibit high selectivity for the different receptors, raising a lot of interesting, still unanswered, questions about the structural requirements of ligand-receptor interaction for agonist activity and about the common or different intracellular complexes involved in signal transduction. The picture is getting broader and more detailed, mostly thanks to in vitro studies.In vivo studies on the neurological effects of cytokines of the IL-1
structural superfamily, like that by Kubota et al. (28) or
this study, could also contribute to the effort of understanding the
biology of the system. If IL-18 is a modifier of IL-1 response, this
effect could be important, especially considering that IL-1/ are
the most potent among the pyrogenic, anorectic, and somnogenic substances we know.
Fever, in particular, is a stereotyped and phylogenetically very ancient reaction to infection. The knowledge concerning other proinflammatory cytokines of the IL-1 structural superfamily and their effect on IL-1-induced fever is also of importance for our understanding of the molecular mechanisms inducing and sustaining the pyrogenic response both in the periphery and at the hypothalamic level.
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ACKNOWLEDGEMENTS |
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This study was supported in part by National Institutes of Health Grant AI-15614 (to C. A. Dinarello).
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FOOTNOTES |
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Present address of T. Bartfai: "Harold L. Dorris" Neurological Research Center, Dept. of Neuropharmacology, Scripps Research Institute, 10550 N. Torrey Pines Rd., SR-307, La Jolla, CA 92037.
Address for reprint requests and other correspondence: S. Gatti, Hoffmann-LaRoche PRBN-P, Bldg.68, Rm.40B, CNS Preclinical Research, Pharmaceutical Division, Grenzacherstrasse, CH-4070 Basel, Switzerland (E-mail: silvia.gatti{at}roche.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00393.2001
Received 9 July 2001; accepted in final form 11 October 2001.
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RESULTS
DISCUSSION
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