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Vol. 282, Issue 2, 873-881, 1997
- and Prostaglandin E-Induced Fevers in Rats: Possible
Involvement of Brain Angiotensin II Receptor in Fever
Induction1
The Department of Physiology, Yamaguchi University School of Medicine, Ube Yamaguchi 755, Japan
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Abstract |
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 Top
Abstract
Introduction
Methods
Results
Discussion
References
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We investigated the role of the brain angiotensin II (Ang II) receptor
subtypes AT1 and AT2 in the
development of fever induced in freely moving rats by administration of
interleukin-1
(IL-1) or prostaglandin E2
(PGE2). Intraperitoneal (i.p.) injection of IL-1 (2 µg/kg) induced a marked fever of rapid onset.
Intracerebroventricular (i.c.v.) administration, immediately before
IL-1 injection, of a selective AT2 receptor
antagonist, CGP42112A (5 or 20 µg), reduced the fever in a
dose-related manner. Rats given an i.c.v. injection of
PGE2 (200 ng) developed a monophasic fever
response that was attenuated by i.c.v. treatment with CGP42112A (10 or
20 µg) in a dose-related manner. The IL-1 (2 µg/kg i.p.)- and
PGE2 (200 ng i.c.v.)-induced fevers were
unchanged by the selective AT1 receptor
antagonist losartan (60 µg i.c.v.). Treatment with exogenous Ang II
(100 ng i.c.v.), which itself had no effect on resting body
temperature, resulted in an enhancement of the
PGE2 (50 ng i.c.v.)-induced fever. The
administration of CGP42112A (2 and 5 µg) into the rostral
hypothalamus (preoptic/anterior hypothalamic region) reduced fevers
induced by IL-1 (2 µg/kg i.p.) or intrahypothalamic (i.h.)
PGE2 (100 ng). Moreover, i.h. injection of Ang II
(25 ng) augmented the PGE2 (25 ng i.h.)-induced
fever. Finally, the i.h. administration, 15 min before i.h.
PGE2 (100 ng), of the angiotensin-converting enzyme (ACE) inhibitor lisinopril (5 and 10 µg) attenuated the PGE2-induced fever. These results suggest that
brain AT2 receptors contribute to the induction
of such febrile responses in rats.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Brain
Ang II plays important roles in physiological control processes such as
blood pressure regulation and fluid homeostasis (Phillips, 1987
; Wright
and Harding, 1992). In addition, it was suggested in the 1980s that
brain Ang II participates in thermoregulatory responses. Thus, central
injections of Ang II were shown to lower resting body temperature
(Chern and Lin, 1981; Lin, 1980; Shido et al., 1985; Wilson
and Fregly, 1985), suggesting that Ang II acts as a
temperature-lowering substance in the brain. However, Shido et
al. (1985) showed that Ang II-induced hypothermia was inhibited by
sinoaortic denervation, indicating that the hypothermia might be
secondary to a nonspecific baroreflex inhibition of the sympathetic
nervous system, itself evoked by the pressor effect of Ang II. For that
reason, it is now difficult to evaluate the earlier observations. More
recent evidence suggests a different role for Ang II. For example,
Takahashi et al. (1988) reported that i.c.v. injection of
the nonspecific Ang II receptor antagonist attenuates the hyperthermia
induced by an i.c.v. injection of a pyrogen, penicillin. In addition,
we have recently shown an attenuation by central Ang II receptor
blockade of stress-induced hyperthermia (Saiki et al.,
1997). Thus, it now seems likely that endogenous brain Ang II
contributes to the production of increases in body temperature rather
than decreases, possibly via activation of the sympathetic
nervous system (Saiki et al., 1997).
IL-1, a cytokine produced during infection and inflammation, is well
known to induce fever by its action on the brain, where it stimulates
the secretion of PGE, which causes fever, possibly as a final mediator
(Dinarello, 1984; Kluger, 1991). Interestingly, it has been reported
that IL-1, given systemically, activates the renin-angiotensin system
(Bataillard et al., 1992) and that the circulating Ang II
may then act on circumventricular organs, particularly the subfornical
organ, from which Ang II pathways to several brain regions may be
activated (Lind et al., 1984; Wright and Harding, 1992).
Moreover, the involvement of prostaglandins has been suggested in this
activation of the renin-angiotensin system (Antonipillai et
al., 1990; Bataillard et al., 1992). Having considered
these pieces of evidence, we wondered in what way endogenous brain Ang
II might participate in febrile responses. Because recent studies have
revealed the existence of two types of Ang II receptor in the brain,
AT1 and AT2 (Saavedra,
1994), we decided to investigate the effect of the central injection of
AT1 and AT2 receptor
antagonists on febrile responses induced in rats by i.p. injection of
IL-1 or central injection of PGE2.
Furthermore, the effect of the central administration of Ang II and of
an ACE inhibitor was examined on the PGE2-induced
fever. The present results suggest that AT2 receptors, but not AT1 receptors, play an
important role in the development of febrile responses in rats.
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animals
The animals used in this study were male Wistar rats, weighing 270 to 350 g. They were housed in individual plastic cages (40 × 25 × 25 cm; length × width × depth) with wood-chip bedding in a room maintained at 26 ± 1°C, a temperature within the thermoneutral zone for rats. They experienced a 12-hr light/dark photoperiod, with lights coming on at 7:00 a.m. All animals had ad libitum access to drink and standard laboratory rat chow. The animals' living conditions and the experimental protocols were in accordance with criteria of the ethics committee of Yamaguchi University.
This study comprised six experiments, all conducted on freely moving rats. Each rat took part in only one experiment. Details of the six experimental protocols are given below.
Surgery
For i.c.v. injections, each rat was implanted with a
stainless-steel cannula (0.8 mm o.d.), which was placed by standard
stereotaxic techniques in the third ventricle at AP 0.2 mm, L 0.0 mm
and V 9.0 mm [coordinates from the rat brain atlas of Pellegrino
et al. (1979)]. For i.h. injections, a similar
stainless-steel cannula was implanted into the PO/AH region on one side
at coordinates AP 1.8 mm, L 1.2 mm and V 8.5 mm. In some occasions, two
cannulae were implanted into the PO/AH region, one on each side. At
least 2 weeks were allowed to elapse before implantation of the
biotelemetry transmitter.
Body temperature was measured using a biotelemetry system (Data
Science, Inc., St Paul, MN) (Lange et al., 1991). Each rat was anesthetized with sodium pentobarbitone (50 mg/kg i.p.), and a
battery-operated transmitter (model TA10TA-F40) was implanted i.p. The
transmitter included a sensor and a radiofrequency transmitter. The
output of the transmitter was monitored by antennae mounted in a
receiver board (model CTR86) placed under each animal's cage. The data
were fed into a peripheral processor (matrix model BCM100) connected to
a Sanyo MBC-17J AX computer (IBM compatible). The implantation of the
transmitter was performed 
1 week before the start of the experiment.
All rats were handled for 15 min each day for 5 days to accustom them
to the experimenters. This procedure is very important to prevent the
animals from developing stress-induced hyperthermia after any
injections.
Drugs
Human recombinant IL-1, supplied by Otsuka Pharmaceutical
(Tokushima, Japan), was produced from recombinant strains of
Escherichia coli. The activity of the IL-1 was found to
be 2 × 104 units/µg by a thymocyte
coproliferation assay. The IL-1 preparation was shown to be free of
significant endotoxin contamination by the Limulus
amoebocyte assay (<0.05 pg/µg of protein). For injection purposes,
the recombinant IL-1 was dissolved in sterile saline, with the
solution divided between several vials and stored at 
40°C until
needed. We used the entire contents of a given vial within the 2 days
after thawing and thus avoided repeated freezing and thawing.
PGE2 (Sigma Chemical, St. Louis, MO) was
dissolved in ethanol and this solution was stored at 40°C. When
used, an aliquot of the PG solution was dried under nitrogen gas, and
the resulting pellet was dissolved in aCSF (128 mM NaCl, 2.6 mM KCl, 1.3 mM CaCl2, 0.9 mM MgCl2,
20 mM NaHCO3, 1.3 mM
NaH2PO4, pH 7.4). Losartan
(a kind gift from Dupont Merck Co. Ltd., Rahway, NJ), CGP42112A
(Neosystem Laboratory, Strasbourg, France), lisinopril (Sigma) and Ang
II (Sigma) were dissolved in aCSF. Injection doses for each
experimental group are given in Results.
Experimental Protocols
All recordings were made from freely moving rats in their home cages. Rats were deprived of water and feed during the experiment itself. On the day of the experiment, each rat was gently picked up, and its transmitter was switched on using a magnet. The body temperature was then allowed to stabilize for a period of 90 min before any injections.
Experiment 1.
The effect was examined of i.c.v. injection of
the AT2 receptor antagonist CGP42112A on fever
induced by IL-1 or PGE2. IL-1 was
administered i.p. in a volume of 1 ml/kg over a period of 15 sec into
hand-held rats. To minimize the confusing effects of the rats'
circadian rhythm, IL-1 was always given between 10:00 and 11:00 a.m.
Either aCSF or one of the two doses of CGP42112A (5 and 20 µg) was
given by i.c.v. injection immediately before the IL-1 to examine
their effect on the induced fever. The i.c.v. injections were made
via a stainless steel needle (0.4 mm o.d.) inserted through
the cannula and attached to a microsyringe via polyethylene
tubing. These injections were performed in a volume of 5 µl over a
period of 30 sec. Another group of rats were given PGE2 i.c.v. to induce fever. Either aCSF or one
of three doses of CGP42112A (5, 10 and 20 µg) was given i.c.v. to
each animal just before the PGE2. The total
volume of the i.c.v. injections was always 5 µl/rat. To confirm that
the effect of i.c.v. CGP42112A on fever was not due to leakage into the
peripheral circulation, i.v. injections of the drug (20 µg) and aCSF
were performed just before the injection of IL-1 or
PGE2.
Experiment 2.
The effect of i.c.v. injection of the
AT1 receptor antagonist losartan (60 µg) was
examined on either IL-1- or PGE2-induced fever. The procedures used were essentially the same as those described
for experiment 1.
Experiment 3. The effect of the i.c.v. injection of Ang II was examined on the fever induced by i.c.v. PGE2. The injection of Ang II was given just before that of PGE2. The total volume of the i.c.v. injections was always 5 µl/rat.
Experiment 4.
The effect of the i.h. injection of either
aCSF or one of two doses of CGP42112A (2 and 5 µg) was investigated
on either IL-1- or PGE2-induced fever. IL-1
(2 µg/kg) was administered i.p., and PGE2 (100 ng) was administered i.h. The rats received CGP42112A immediately
before the IL-1 or PGE2. The i.h. injections
were given unilaterally in a total volume of 500 nl over a period of 30 sec. In some occasions, bilateral i.h. injections of the antagonist were given immediately before the i.p. injection of IL-1. The drug
was administered at a dose of 2.5 µg in a volume of 500 nl on each
side (i.e., total dose per rat was 5 µg).
Experiment 5. The effect was examined of the i.h. injection of Ang II on the fever induced by i.h. PGE2. The rats received Ang II (25 ng) immediately before PGE2 (25 ng). The total volume of the i.h. injections was always 500 nl/rat.
Experiment 6. The effect of an i.h. injection of aCSF containing one of two doses of the angiotensin-converting enzyme inhibitor lisinopril (5 and 10 µg) was examined on PGE2 (100 ng i.h.)-induced fever. The injection of lisinopril was performed in a volume of 500 nl at ~15 min before the PGE2 injection (100 ng in 500 nl i.h.).
Histological Verification
After its involvement in experiment 1, 2 or 3, each animal was killed with an overdose of pentobarbitone. Carbon solution (5 µl; Rotering, Hamburg, Germany) was then injected i.c.v. to mark the ventricular space. The brain sections were visually examined to verify that the tip of the stainless-steel cannula had indeed been located in the third cerebral ventricle.
After the completion of experiments 4, 5 and 6, the placement of the cannula was confirmed by histological examination. Only data from animals in which the cannula proved to be located within the PO/AH region have been included in the Results. In this study, ~10% of the rats were excluded from the study on the basis of the histological results.
Statistical Analysis
All results are expressed as mean ± S.E.M. Data were analyzed for statistical significance by a repeated-measures analysis of variance, followed by Scheffé's test (post hoc test) (Macintosh, StatView 4.0). Analysis was performed on data collected from the time of drug injection onward (i.e., from time 0). Differences were considered significant at levels of P < .05.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Effect of i.c.v. treatment with an AT2
receptor antagonist on IL-1- or PGE2-induced
fever in rats (experiment 1).
Figure
1 shows the effect of i.c.v. injection of
CGP42112A on fever induced by IL-1 (fig. 1A) or
PGE2 (fig. 1B). The injection of IL-1 (2 µg/kg i.p.) in the aCSF-treated controls resulted in a biphasic
increase in body temperature (fig. 1A), which began after 5 min and
reached its first peak at 30 to 35 min. This increase in body
temperature was attenuated by treatment with CGP42112A (5 or 20 µg
i.c.v.) in a dose-related manner, with the effect significant at P < .05 [CGP42112A (5 µg) + IL-1, 0-35 min; CGP42112A (20 µg) + IL-1, 0-115 min].
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and i.c.v. injection
of aCSF, the vehicle for PGE2, had no marked
effect on body temperature in our rats (which were well-accustomed, by
repeated handling, to the experimenters). The relevant data are shown
in table 1.
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(2 µg/kg i.p.)- or PGE2 (200 ng i.c.v.)-induced
fever between CGP42112A (20 µg) and aCSF when each was administered
i.v. The relevant data for IL-1- and
PGE2-induced fevers are shown in tables
2 and 3,
respectively.
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Effect of i.c.v. treatment with an AT1
receptor antagonist on IL-1- or PGE2-induced
fever in rats (experiment 2).
As shown in figure
2, i.c.v. treatment with losartan (60 µg) had no effect on the febrile response induced by either IL-1 (2 µg/kg i.p.) or PGE2 (200 ng i.c.v.). This
dose of losartan (60 µg) is actually rather high because <10 µg of
the drug is sufficient to inhibit Ang II-induced responses such as
increases in water intake (Rowland et al., 1992) and
arterial blood pressure in rats (Hogarty et al., 1992).
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Effect of i.c.v. treatment with Ang II on
PGE2-induced fever (experiment 3).
Before
assessing its effect on induced fever, we examined the effect of
exogenous Ang II on resting body temperature. As depicted in figure
3, aCSF-injected controls showed a slight
increase (~0.3°C) in resting body temperature. The lower dose of
Ang II (100 ng i.c.v.) caused no change in this temperature response,
whereas the higher dose (5 µg i.c.v.) reduced it (P < .05, 0-95 min). Because Ang II at a dose of 100 ng had no effect on resting
body temperature, we used this dose in the subsequent tests.
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Effect of i.h. treatment with an AT2
receptor antagonist on IL-1- or PGE2-induced
fever in rats (experiment 4).
The febrile responses induced by
IL-1 (2 µg/kg i.p.) or PGE2 (100 ng i.h)
were both attenuated by i.h. treatment with CGP42112A (2 and 5 µg) in
a dose-related manner, with its effect significant at P < .05 [CGP42112A (5 µg) + IL-1, 0-80 min; CGP42112A (5 µg) + PGE2, 0-40 min] (fig.
5). CGP42112A (5 µg i.h.) given alone had no effect on resting body temperature (fig. 5B).
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(2 µg/kg i.p.)-induced fever. The result showed a
suppression of the fever by the drug (P < .05, 0-75 min). The
relevant data are shown in table 4.
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Effect of i.h. treatment with Ang II on
PGE2-induced fever (experiment 5).
Before
assessing its effect on induced fever, the effect was examined of an
i.h. injection of Ang II on resting body temperature (fig.
6). In fact, Ang II at a low dose (25 ng
i.h.) had no effect on resting body temperature over and above any
changes seen on aCSF administration. A higher dose of Ang II (5 µg
i.h.) tended to lower the body temperature changes seen in
aCSF-injected control rats, but this effect was insignificant.
Moreover, the high dose of Ang II (5 µg i.h.) did not induce
hypothermia. Because Ang II at a dose of 25 ng had no effect on the
resting body temperature, we used this dose in the subsequent tests.
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Effect of i.h. pretreatment with an angiotensin-converting enzyme
inhibitor on PGE2-induced fever in rats
(experiment 6).
Figure 8 shows the
effect of i.h. pretreatment with lisinopril on
PGE2-induced fever. Lisinopril (5 or 10 µg
i.h.) or aCSF was given 15 min before the injection of
PGE2 (100 ng i.h.). As shown in figure 8, the
PGE2-induced fever was reduced by pretreatment with lisinopril in a dose-related manner, with the effect significant at P < .05 [lisinopril (10 µg) + PGE2,
0-75 min].
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The present results show that the fever induced by i.p. IL-1
was attenuated in rats by i.c.v. treatment with an
AT2 receptor antagonist, CGP42112A, as was the
fever due to i.c.v. injection of PGE2. In
contrast, an AT1 receptor antagonist, losartan,
had no effect on the fevers. These results suggest that
AT2 receptors, rather than
AT1 receptors, in the brain play some role in the development of IL-1- and PGE2-induced fevers
in rats. Furthermore, exogenous Ang II (100 ng i.c.v.), which itself
had no effect on resting body temperature, enhanced the
PGE2-induced fever. Therefore, it is likely that
central Ang II modulates PGE2-induced fever in
rats. This should lead to a modulation of IL-1-induced fever as
well, because PGE2 is considered to be the final
mediator of fever production (Dinarello, 1984). Interactions between
central Ang II and catecholamines, serotonin and other transmitters
have been suggested by others (see Phillips, 1987). For example, Ang II
enhances field stimulation-induced release of norepinephrine from rat
brain tissue in vitro (Meldrum et al., 1984).
Therefore, it is possible that central Ang II interacts in some way
with transmitters involved in the mediation of fever induction.
Because a drug injected i.c.v. can potentially reach the entire brain,
we could not determine the brain site responsible for the observed
effect of CGP42112A when the drug was given by that route. For that
reason, we conducted another experiment in which the drug was injected
into the rostral hypothalamus (PO/AH region), the possible site at
which PGE2 acts to produce fever (Dinarello, 1984; Kluger, 1991). The results showed that i.h. injection of the
AT2 receptor antagonist reduced the fever induced
by either i.p. IL-1 or i.h. PGE2. Moreover,
the PGE2-induced fever was augmented by i.h.
treatment with Ang II. These results suggest that an Ang II-sensitive
site in the rostral hypothalamus may participate in the induction of
febrile responses in rats. Furthermore, i.h. pretreatment with the
angiotensin-converting enzyme inhibitor, lisinopril, attenuated the
PGE2-induced fever in this study. It is therefore
likely that the activity of the central renin-angiotensin system
contributes, at least in part, to the induction of such fever.
There is a report that i.c.v. administration of penicillin induced an
elevation in body temperature that was attenuated by i.c.v. injection
of the nonspecific Ang II receptor antagonist, 1-Sar,8-Ile-Ang II
(Takahashi et al., 1988). In addition, we recently showed an
inhibition of stress-induced hyperthermia by central AT1 receptor blockade, although we did not
explore the effect of an AT2 receptor antagonist
(Saiki et al., 1997). These findings imply an involvement of
central Ang II in hyperthermia and, in that sense, are in accord with
the present results indicating that central Ang II may play an
important role in body temperature elevation. However, in the present
study, an AT2 receptor antagonist, but not an
AT1 receptor antagonist, reduced the fevers.
Therefore, it is likely that AT1 receptors
participate in stress-induced hyperthermia but not in the types of
fever studied here. In other words, the exact mechanisms involved in
the induction of stress-induced hyperthermia (Saiki et al.,
1997) and IL-1- or PGE2-induced fever are not
the same, although central Ang II appears to participate in both cases
in the rise in body temperature, at least in rats. We have previously
shown that systemic blockade of PG synthesis by indomethacin completely
inhibits IL-1-induced fever (Watanabe et al., 1991), whereas
it only partially attenuates stress-induced hyperthermia (Morimoto
et al., 1991). Furthermore, the involvement of brain CRF has
been suggested in stress-induced hyperthermia but not in the fevers
induced by i.p. IL-1 or i.c.v. PGE2 (Nakamori et al., 1993). These results indicate that PGs are the
principal mediators of IL-1-induced fever, whereas CRF as well as PGs
participate in the development of stress-induced hyperthermia. Thus,
the involvement of brain CRF may be specific to stress-induced
hyperthermia. Taken together, these findings may suggest that brain CRF
neurons are stimulated during stress by Ang II acting on
AT1 receptors, resulting in stress-induced
hyperthermia. Indeed, it has been reported that CRF neurons in the
paraventricular nucleus express AT1 receptor mRNA
and that the expression of CRF mRNA is enhanced by the central administration of Ang II (Aguilera et al., 1995). On the
other hand, it is possible that AT2 receptors
also participate in stress-induced hyperthermia, because prostaglandins
partially mediate this type of hyperthermia. This possibility should be
examined in future research.
Some years ago, it was reported (Shido et al., 1985; Wilson
and Fregly, 1985) that i.c.v. administration of Ang II lowers resting
body temperature in rats. These findings are not in agreement with ours
(obtained with i.c.v. injection of Ang II at 100 ng plus
PGE2). However, it should be noted that those
previous studies used extremely high doses of Ang II (1-5 µg
i.c.v.), which presumably would markedly increase blood pressure and
thus produce a baroreceptor reflex. Indeed, Shido et al.
(1985) demonstrated that i.c.v. injection of Ang II (5 µg) in rats
induced baroreflex bradycardia as well as hypothermia and that
sinoaortic denervation reduced the hypothermia. These results suggest
that inhibition of sympathetic nervous activity by the baroreceptor
reflex, which would lead to a reduction in heat production in metabolic
tissues, is principally responsible for the Ang II-induced hypothermia.
Therefore, it is likely that the induction of hypothermia is not a
direct effect of Ang II. We, too, observed a slight hypothermia when we
used the same high dose of Ang II (5 µg i.c.v.). However, i.h.
administration of this high dose of Ang II (5 µg) did not produce
hypothermia, indicating that the peptide does not act on the neural
networks in the rostral hypothalamus (PO/AH region) to reduce resting
body temperature in rats. In this study, a smaller dose of Ang II
enhanced the PGE2-induced fever. The doses of Ang
II (100 ng i.c.v. and 25 ng i.h.) that we used to show potentiation of
PGE2-induced fever were chosen on the basis of
the following criteria. (1) The dose should have no effect on resting
body temperature. (2) The dose should be one that is considered to be
an adequate stimulus for Ang II receptors. In fact, at 100 ng i.c.v. or
25 ng i.h., Ang II did not affect resting body temperature in this
study. However, it has been reported that at 100 ng i.c.v., Ang II
induces a pressor effect (Stadler et al., 1992; Tsukashima
et al., 1996) and that at 25 ng i.h., it produces
a dipsogenic response in rats (Bastos et al.,
1994). Thus, the doses of Ang II chosen for this study satisfy the above criteria.
In this study, the fever induced by IL-1 or
PGE2 was attenuated by central Ang II receptor
blockade, suggesting the participation of central Ang and Ang II
receptors in the induction of the fever. The mechanism underlying the
activation of the central Ang II system during an IL-1-induced fever
was not explored here. However, we know that IL-1 has been reported to
stimulate the renin-angiotensin system (Antonipillai et al.,
1990; Bataillard et al., 1992). It is possible that the
resulting circulating Ang II, having reached circumventricular organs
(CVO) such as the subfornical organ, may directly or indirectly
stimulate Ang II neurons projecting from the CVO to other brain
regions, such as the rostral hypothalamus. This speculation is
supported by the finding that circulating Ang II exerts a portion of
its actions via stimulation of brain Ang II receptors
located in the subfornical organ (Wright and Harding, 1992), a
structure that sends Ang II projections to the rostral hypothalamus
(Lind et al., 1984). In this way, the release of brain Ang
II could be stimulated during fever induced in rats by the systemic
administration of IL-1. On the other hand, it has been reported that
PGE2 stimulates renin release from the kidney
(Bugge, 1989) and that a separate and distinct renin-angiotensin system
is present within the brain (Phillips, 1987; Wright and Harding, 1992).
If this is true, the central injection of PGE2 might lead to the release of brain Ang II through the activation of the
brain renin-angiotensin system. The present finding that i.h. injection
of an ACE inhibitor reduced the PGE2-induced
fever favors this hypothesis. The presence of an active
renin-angiotensin system in the rostral hypothalamus has also been
detected by other researchers who showed that ACE blockade in the
preoptic area resulted in a suppression of the water intake induced by
water deprivation (Saad et al., 1993).
The distribution of Ang II receptor subtypes has been demonstrated in
many brain nuclei by autoradiographic methods (Rowe et al.,
1992; Tsutsumi and Saavedra, 1991). However, to our knowledge, there
have been no reports indicating whether Ang II receptors exist in
nonnuclear brain regions, such as the PO/AH region, which has been
suggested to play a crucial role in fever production (Dinarello, 1984;
Kluger, 1991). Nevertheless, injection of Ang II into the PO/AH region
has been shown to induce physiological responses such as increased
water intake (Bastos et al., 1994; Shibata et
al., 1993), suggesting the existence of Ang II receptors in this
region. Furthermore, both the existence and the localization of
AT1 and AT2 receptors have
been demonstrated in hypothalamic membranes (Leung et al.,
1991). In our rats, an attenuation of induced fever was produced by
injection of an Ang II type-2 receptor antagonist into the rostral
hypothalamus. Taken together, this evidence leads us to propose that
AT2 receptors in the rostral hypothalamus make
some contribution to the induction of the fever induced in rats by
administration of IL-1 or PGE2. Interestingly, mice that lack the AT2 receptor gene ("knockout
mice") have a lower resting body temperature than their controls
(Ichiki et al., 1995). This observation lends support to the
idea that AT2 receptors participate in body
temperature regulation. However, more work needs to be done to test
this hypothesis by, for example, looking for changes in the brain Ang
II concentration during fever. It would also be interesting to examine
whether changes occur in the activity of the brain renin-angiotensin
system and in the Ang II receptor subtypes during fever. This should be
possible in the near future using immunohistochemistry and in
situ hybridization techniques.
Finally, CGP42112A, which was used as an AT2
receptor antagonist in this study, has repeatedly been shown to have an
antagonistic action at AT2 receptor sites
(Hogarty et al., 1994; Rowland et al., 1992;
Sumners et al., 1991; Zarahn et al., 1992).
However, there are several reports indicating that CGP42112A could act as an agonist at some AT2 receptors, such as
those involved in the regulation of the cerebral circulation (Naveri,
1995; Naveri et al., 1994) and in the control of vascular
cell proliferation (Stoll et al., 1995). For this reason, we
must keep in mind the possibility that CGP42112A may act as an agonist
in some systems or under some conditions. In this study, IL-1- and
PGE2-induced fevers were inhibited by CGP42112A but not by
an AT1 receptor antagonist. Moreover,
PGE2-induced fever was augmented by Ang II and
inhibited by an ACE inhibitor. All these results indicate that
CGP42112A was acting as an antagonist in this study and that AT2 receptors are indeed involved in fever
induction. However, it should be interesting to examine the effect of
an AT2 receptor agonist on fevers in future
studies before any final conclusion is reached.
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Acknowledgments |
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We are grateful to Dr. Shoji Nakamura for his invaluable
suggestions and comments. We would also like to acknowledge the
critical reading of the English manuscript by Dr. Robert J. Timms. We
thank Otsuka Pharmaceutical and Dupont Merck Co. Ltd. for the supply of
human recombinant IL-1 and losartan, respectively.
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Footnotes |
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Accepted for publication April 1, 1997.
Received for publication September 10, 1996.
1 This work was partly supported by the Ministry of Education, Science and Culture with a Grant-in-Aid for Scientific Research (C08670083).
Send reprint requests to: Tatsuo Watanabe, M.D., Ph.D., Department of Physiology, Yamaguchi University, School of Medicine, Ube, Yamaguchi 755, Japan.
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Abbreviations |
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IL-1, interleukin-1; CRF, corticotropin-releasing factor; PGE2, prostaglandin E2; PO/AH, preoptic/anterior hypothalamic; aCSF, artificial cerebrospinal fluid; Ang II, angiotensin II; i.p., intraperitoneal; i.c.v., intracerebroventricular; i.h., intrahypothalamic; i.v., intravenous.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Am. J. Physiol.
265: R834-R839, 1993
-human atrial natriuretic polypeptide at the preoptic area in spontaneously hypertensive rats.
Arch. Int. Pharmacodyn.
322: 23-34, 1993.This article has been cited by other articles:
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P < .05 aCSF + IL-1
