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1 Department of Pediatrics and the 2 Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, Florida 33101
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Central administration of
interleukin-1
(IL-1) increases cerebral blood flow (CBF) and body
temperature, in part, through the production of prostaglandins. In
previous studies, the temporal relationship between these effects of
IL-1 have not been measured. In this study, we hypothesized that the
increase in CBF occurs before any change in brain or body temperature
and that the cerebrovascular and thermoregulatory effects of IL-1
would be attenuated by inhibiting the production of nitric oxide (NO).
Adult male rats received 100 ng intracerebroventricular (icv) injection
of IL-1, and cortical CBF (cCBF) was measured by laser-Doppler in
the contralateral cerebral cortex. A central injection of IL-1
caused a rapid increase in cCBF to 133 ± 12% of baseline within
15 min and to an average of 137 ± 12% for the remainder of the
3-h experiment. Brain and rectal temperature increased by 0.4 ± 0.2 and 0.5 ± 0.2°C, but not until 45 min after IL-1
administration. Pretreatment with N
-nitro-L-arginine methyl ester
(L-NAME; 5 mg/kg iv) completely prevented the changes in
cCBF and brain and rectal temperature induced by IL-1.
L-Arginine (150 mg/kg iv) partially reversed the effects of
L-NAME and resulted in increases in both cCBF and temperature. These findings suggest that the vasodilatory effects of
IL-1 in the cerebral vasculature are independent of temperature and
that NO plays a major role in both the cerebrovascular and thermoregulatory effects of centrally administered IL-1.
cytokines; cerebral blood flow; vasodilation; brain; fever; temperature; inflammation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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INTERLEUKIN-1
(IL-1), a 17-kDa polypeptide possessing a wide spectrum of
inflammatory, metabolic, physiological, hematopoietic, and immunologic
activities, is produced by a variety of cells, including lymphocytes,
mononuclear phagocytes, and endothelial cells (13).
Intracerebroventricular (icv) injection of IL-1 causes pituitary
adrenal activation, hyperinsulinemia, slow-wave sleep, behavioral
changes, hypophagia, glial proliferation, neovascularization, peripheral neutrophilia, and fever (6, 10-13, 22, 31,
35). In a normal brain, low amounts of IL-1 have been
identified in microglia, astrocytes, and vascular endothelial cells,
predominantly in the hypothalamus, pituitary gland, hippocampus, and
cerebral cortex (47). IL-1 is produced in the brain in
response to central nervous system (CNS) and systemic infections
(19, 25) and to ischemic (32, 45, 48)
and traumatic brain injury (42), conditions that are
associated with both fever and alterations in cerebral blood flow (CBF)
(9, 16, 17).
Cerebral vasodilation after IL-1 injection has been shown to be
mediated, in part, by the prostaglandins, 6-keto-PGF1
, PGE2, and PGF2, through activation of
cyclooxygenase-1 (COX-1) and COX-2 (23, 36, 41). These
prostanoids are thought to cause early cerebral vasodilation by
accumulation of cyclic nucleotides (4) and, later, by
stimulation of the inducible form of nitric oxide (NO) synthase (iNOS)
in vascular smooth muscle and endothelial cells, thereby increasing the
production of NO (7, 14, 21).
In the CNS, the cells that have been found to be capable of NO
production include astrocytes, microglia, neurons, and endothelial cells. Neurons containing NOS have been identified in brain regions that participate in thermoregulation, such as the hypothalamic nuclei
and circumventricular organs, suggesting that NO may play a central
role in the regulation of temperature (3, 30, 39, 46).
Inhibition of NOS in experimental animal models of sepsis has
attenuated the height and duration of fever, providing indirect evidence that NO mediates the febrile response to IL-1 (15, 34, 37). However, the exact role of NO in thermoregulation has
not been clearly delineated (40).
Because the effect of temperature on the cerebrovascular response to
IL-1 has not been previously investigated, we designed the present
study to investigate the relationship between the cerebrovascular and
thermoregulatory responses to central injection of IL-1, and to
determine the role of NO in these responses. We hypothesized that
1) central injection of IL-1 increases cortical CBF
(cCBF) and brain and body temperature, 2) the
vasodilatory effects of IL-1 are independent of temperature, and
3) inhibition of NOS by L-NAME attenuates
the changes in CBF and temperature after central administration of
IL-1.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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This study was approved by the University of Miami Animal Care
and Use Committee. Young adult (2-3 mo) male Sprague-Dawley rats
were anesthetized with 5% isoflurane-70% nitrous oxide
(N2O), balance oxygen, and were endotracheally intubated
and ventilated with a rodent respirator (model 50095-1, Stoelting;
Wood Dale, IL) to achieve normal arterial blood gases. Anesthesia was
maintained with 1-2% isoflurane-70% N2O, balance
oxygen, and the rats were paralyzed with pancuronium (1 mg · kg
1 · h1 iv). The
femoral vessels were catheterized for measurement of mean arterial
pressure (MAP), blood sampling, and drug administration. A thermocouple
probe was inserted into the rectum to a distance of 8 cm for continuous
temperature monitoring, and then the animal was placed in a
stereoctatic frame to immobilize the cranium. The dorsal scalp was
reflected from 3 mm anterior to bregma to the posterior neck muscles. A
1-mm-diameter craniotomy was made 2 mm posterior and 3 mm lateral to
bregma on the right, through which a 30-gauge thermocouple probe was
inserted to a depth of 2 mm so that its tip would lie within the
cerebral cortex. A second craniotomy was made on the right 0.8 mm
posterior and 1.5 mm lateral to bregma for icv injection into the right
lateral ventricle. Icv injections (10 µl) were made by using a
micropipette at a depth of 4 mm into the right lateral ventricle over 2 min to prevent changes in intracranial pressure. On the left, a third
craniotomy, measuring 2 × 3 mm, was made 2 mm posterior and 3 mm
lateral to the bregma, exposing the intact dura. All of the
craniotomies were made under saline irrigation down to a thin layer of
bone, which was then excised with microforceps. To measure cCBF, a
0.8-mm-diameter laser-Doppler flow probe was positioned with a
micromanipulator adjacent to the dura over an area free of large
vessels in the lateral parietal cortex and connected to a tissue
perfusion monitor (model ALF-21D, Transonic Systems; Ithaca, NY).
The arterial catheter was connected to a Statham pressure transducer (model 13-4615-50, Gould; Cleveland, OH), which was calibrated before each experiment. Measurements of arterial blood pressure and cCBF were recorded continuously (model RS3600, Gould). Arterial blood gases and pH, and plasma glucose and lactate concentrations were measured hourly (model YSI 2300, Yellow Springs Instruments). Brain and rectal temperatures were recorded every 15 min.
After all of the surgical manipulations had been completed, isoflurane, but not N2O, was discontinued. The next 60 min were used to establish a stable baseline temperature and cCBF. During this time, rectal and brain temperatures were kept at 37.5 ± 0.3°C with the use of heating lamps. Once temperature stability was achieved, the position of the heating lamps was held constant for the remainder of the experiment.
The experiment was divided into two phases. The first phase was a
prospective, blinded study with two experimental groups. Group
I (n = 7) received 100 ng icv of heat-inactivated
IL-1 (75°C for 2 h) in artificial CSF. Group II
(n = 7) received 100 ng icv of recombinant rat IL-1
(Endogen; Woburn, MA) in artificial CSF. A single dose of IL-1 100 ng icv was chosen because in pilot studies this dose consistently
caused a significant and sustained increase in both CBF and rectal
temperature, as opposed to 25 or 50 ng IL-1. Groups
I and II were monitored for 180 min after administration of IL-1. In the second phase of the study,
Group III (n = 8) received
L-NAME 5 mg/kg iv 20 min before IL-1 (100 ng icv), and
the responses were monitored for 105 min. At minute 105, a
L-arginine 150 mg/kg iv bolus was given, followed by a continuous infusion 150 mg · kg1 · h1 iv for 75 min
to reverse the effects of L-NAME.
At the end of 3 h, the animals were euthanized with an overdose of
anesthetic and intravenous potassium chloride. Immunohistochemistry for
IL-1 was performed in four animals randomly selected from group II at 30, 45, and 60 min after icv injection of
IL-1, by using a polyclonal antibody to rat IL-1 (Endogen).
Transcardiac perfusion-fixation of the brain was performed with
ice-cold PBS (pH 7.4) for 1 min and ice-cold 4% paraformaldehyde (pH
7.4) for 5 min. The brains were quickly removed and placed in 4%
paraformaldehyde at 4°C for 24 h and then transferred to PBS
until sectioning. Coronal sections (50 µm) were obtained with the use
of a tissue sectioning device (Vibratome; St. Louis, MO) at four levels
from the anterior striatum to the anterior hippocampus.
Sections were then washed, quenched with H2O2,
and incubated with polyclonal rabbit anti-rat IL-1 (1:200) for
48 h at 4°C. After incubation, sections were washed and
incubated for 1 h with a biotinylated goat anti-rabbit IgG
antibody. They were washed again, incubated in diaminobenzidine
tetrahydrochloride for staining, mounted on glass slides, and examined
under light microscopy.
Measurements of brain and rectal temperature, MAP, and cortical CBF were averaged over 5 min for each time point. Data were analyzed by repeated-measures ANOVA with post hoc Bonferroni test. Values are expressed as means ± SE, with P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There were no significant differences between groups for MAP,
cCBF, arterial blood gases, temperature, and plasma glucose and lactate
at baseline, and PaCO2 was tightly controlled between 35-40 mmHg throughout the experiment in all groups. Fifteen
minutes after icv injection of IL-1, cCBF increased to 133 ± 12% of baseline in group II (P < 0.05).
This increase in cCBF was sustained at an average of 137 ± 12%
of baseline for the remainder of the 3-h experiment (Fig.
1). Heat-inactivated IL-1 caused no
statistically significant changes in either cCBF or brain and rectal
temperature. After IL-1, brain and rectal temperature increased by
0.4 ± 0.2 and 0.5 ± 0.2°C, respectively, over baseline at
45 min after central injection of IL-1 and remained at an average of
0.7 ± 0.2 and 0.9 ± 0.2°C, respectively, above baseline
for the remainder of the experiment (Fig.
2). There was a strong correlation
between brain and rectal temperature (R2 = 0.91, P < 0.01) in all experimental groups, with an
average rectal-brain difference of 0.3°C. The observed increase in
cCBF preceded the observed increase in brain temperature by ~30 min (Fig. 3).
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In group III, L-NAME increased MAP from 128 ± 1 to 156 ± 3 mmHg within 15 min (Fig.
4), lowered rectal temperature from
37.7 ± 0.08 to 37.5 ± 0.09 (P < 0.01), and
did not alter brain temperature. Before IL-1, L-NAME
also reduced cCBF by 20 ± 4% (P < 0.01). In the
presence of L-NAME, IL-1 had no effect on either cCBF or
brain and rectal temperature (Figs. 5 and
6). When
L-arginine was given 105 min after central injection of
IL-1, MAP, cCBF, and brain and rectal temperature returned to
baseline (Figs. 5 and 6).
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Immunohistochemistry revealed IL-1-positive cells in the superficial
cerebral cortex and the periventricular surfaces (Fig. 7). This showed that after the icv
injection, IL-1 was widely distributed over the brain cortex and
periventricular region, with only superficial penetration at the time
points studied. Specificity of the primary antibody was confirmed when
no immunoreaction product was present after preadsorption with
recombinant rat IL-1 at a molar ratio of 1:2.5.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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These data show that the early increase in cCBF after central
injection of IL-1 is independent of temperature and that NO plays a
major role in both the cerebrovascular and thermoregulatory effects of
IL-1. This study is unique in that we measured these two important
effects of IL-1 simultaneously in the same animals. Our findings
support the idea that the pathways for the production of NO and
prostaglandins in response to IL-1 are in series (4, 28, 36,
41) rather than in parallel (34).
The cerebrovascular effects of IL-1 have been studied in a variety
of experimental paradigms. Direct application or superfusion of IL-1
onto cerebral arteries has demonstrated rapid increases in vessel
diameter associated with elevations in CSF concentration of eicosanoids
and cGMP (27, 41, 43). With the use of the closed cranial
window technique on newborn piglets, Shibata et al. (41)
found that IL-1 increased pial arteriolar diameter by 18.6% within
10 min, accompanied by increases in CSF concentrations of prostanoids,
cAMP and cGMP. Osuka et al. (28) measured a 28% increase
in basilar artery diameter 2 h after application of IL-1. In
both of these studies, the vasodilatory effects of IL-1 were
prevented by pretreatment with COX inhibitors, suggesting a role for
both prostanoids and NO in the vasodilation induced by IL-1.
Armstead (4) demonstrated that the vasodilatory effects of
the prostaglandins PGI2 and PGE2 are partially
dependent on NO production, because the NOS inhibitor
L-NAME attenuated prostaglandin-induced vasodilation. Other
investigators have shown that PGD2 plays an important role
in the rat's response to IL-1 (44) and in preventing the upregulation of iNOS in vascular smooth muscle cells
(17). In the present study, we measured a 40% increase in
cCBF 15 min after central administration of IL-1, which was
completely prevented by L-NAME. Such a rapid increase in
cCBF after IL-1 probably reflects activation of cNOS (5, 18,
26) rather than iNOS, because several studies (7, 21,
47) have shown that upregulation of the latter isoform of NOS
does not occur until at least 6 h after administration of IL-1.
The thermoregulatory effects of IL-1 have been well studied;
however, the role of NO in this response has not been clearly delineated [for review, see Schmid et al. (40)]. As is
the case for IL-1-induced vasodilation, PGE2 has been
thought to be the primary mediator of the febrile response to IL-1
(12, 13, 22, 35). More recently, NO has been found to play
an important role in thermoregulation, although conflicting studies
have shown both pyretic and antipyretic effects of NO. Almeida et al.
(1) found that centrally injected L-NAME
increased body temperature and enhanced the febrile response to LPS. In
contrast, systemic administration of either L-NAME or the
neuronal NOS inhibitor 7-nitroindazole lowers body temperature and
inhibits the rise in temperature after LPS infusion (8, 34,
37). Although the systemic vasoconstrictive effects of
L-NAME should decrease heat loss through the skin and thus
elevate core temperature, we found that L-NAME decreased
rectal temperature and prevented the febrile response to central
administration of IL-1. Roth et al. (33) reported
similar results in rabbits that were given both IL-1 and
L-NAME intraperitoneally, the latter at 10× the dose used
in our study. In that study, no attempt was made to reverse the effects
of L-NAME. When L-arginine was given 105 min after L-NAME in our study, both cCBF and temperature
increased significantly to pre-L-NAME values but did not
reach the levels seen in rats that received IL-1 alone. The
incomplete reversal of the effects of L-NAME could have
been due to an inadequate dose of L-arginine, although in
pilot studies in rats in our lab and in infant piglets, complete
reversal of the hemodynamic effects of L-NAME were achieved
with L-arginine at 30× the dose of L-NAME (38). A more likely explanation is that insufficient
IL-1 was present in CSF at the time of reversal with
L-arginine, due to rapid clearance or metabolism of
centrally administered IL-1 (12).
In the absence of L-NAME, IL-1 increased cCBF and,
later, brain and body temperature. The delayed elevation in brain
temperature did not further increase cCBF over the level induced
initially by IL-1. The apparent lack of additive effects of IL-1
and fever on cCBF could be explained by the following possibilities:
1) that IL-1 and fever increase cCBF by the same
mechanism, e.g., through the production of NO, 2) that the
increase in brain temperature was too small to cause a change in cCBF,
and 3) that the laser-Doppler method of measuring CBF was
not sensitive enough to detect a small change in cCBF, which may have
occurred when brain temperature increased after IL-1 was given.
Alternatively, the vasodilatory effects of IL-1 may have been
receding at the same time that the same effects of fever were
beginning, yielding no change in cCBF.
Another interesting issue relates to the separate roles of NO and
prostaglandins in the effects of IL-1 on CBF and temperature. Assuming that both compounds are involved in these effects of IL-1,
the following questions arise concerning their synthetic pathways:
1) are they in series or in parallel;
2) are they convergent or divergent; 3)
which is produced first and in greater amounts; and 4)
are there cell-specific differences in the effect of IL-1 on these
pathways? These questions require further investigation.
In conclusion, we found that the increases in both cCBF and temperature
in response to IL-1 were completely prevented by pretreatment with
the nonselective NOS inhibitor, L-NAME, suggesting that NO
plays an important role in these responses to IL-1. Cortical CBF
increased before hyperthermia occurred, indicating that the early
cerebrovascular effects of IL-1 are independent of temperature. Our
findings underscore the important role of NO in brain disorders such as
meningitis (19, 25), stroke (20, 24, 32, 45, 48), and traumatic brain injury (42) in which
inflammatory cytokines may augment the primary injury as well as cause
disturbances in thermoregulation leading to fever. Whereas the
cerebrovascular effects of NO are clearly vasodilatory in the presence
of IL-1, it appears that the thermoregulatory effects of NO depends
upon the dose and species studied, the route of administration and the
site and cell types in the brain involved in its production and action
(40).
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ACKNOWLEDGEMENTS |
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This study was supported by National Institute of Neurological Disorders and Stroke Grants KO8 NS01890-03 (to J. W. Kuluz) and PO1 NS30291-06A1 (to W. D. Dietrich).
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. W. Kuluz, Dept. of Pediatrics (R-131), PO Box 016960, Miami, FL 33101 (E-mail: jkuluz{at}med.miami.edu).
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.
Received 17 July 2000; accepted in final form 14 November 2000.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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