Special Contribution

Yonago Acta medica 2003;46:83–90

Angiotensin II and Fever in Rodents
Tatsuo Watanabe, Michio Miyoshi and Toshiaki Imoto
Division of Integrative Physiology, Department of Functional, Morphological and Regulatory
Science, Tottori University Faculty of Medicine, Yonago 683-8503 Japan
Angiotensin II (ANG II), a bioactive peptide well known to play an important role inblood-pressure and body-fluid regulation, participates in inflammatory responses, too.
Recently, we reported results suggesting that ANG II is involved in the development of thefever induced by intravenous (i.v.) injection of lipopolysaccharide (LPS, 2 µg/kg) indehydrated rats (in which the secretion of ANG II is elevated). Furthermore, we verified
the contributions made by ANG II and its type 1 receptor (AT1 receptor) to the LPSinduced production of interleukin-1β (IL-1β) in those rats. It therefore seems likely thatin rats, ANG II and its receptors contribute to the induction of this fever at its 1st step
(namely, the LPS-induced production of pyrogenic cytokines such as IL-1β). Moreover,
we have revealed that intrahypothalamic (i.h.) ANG II and AT2 receptors are involved in
the development of the fever induced by i.h. injection of prostaglandin E2 (PGE2), a final
fever mediator. ANG II given i.h., which had no effect on the resting body temperature,facilitated PGE2-nduced fever. These results suggest that in rats, ANG II and its receptors
contribute to the induction of fever at its final step, too (namely, the action of PGE2 tocause fever). Finally, a single i.p. injection of IL-1β results in a weaker IL-1β-induced
fever in AT2-receptor-deficient mice than in wild-type mice, suggesting that the brain AT2
receptor is involved in the development of fever (possibly at its final step) in mice as well.
Collectively, these results suggest that in rodents, ANG II and its receptors contribute to
the development of fever, both at the 1st and final steps in the pathway for fever induction.
Key words: AT1 receptor; AT2 receptor; interleukin-1; lipopolysaccharide; prostaglandin E2

Angiotensin II (ANG II), a bioactive peptide wellknown to play an important role in blood-pressure
and body-fluid regulation, seems to participate ininflammatory responses, too. For example, ANG II
and ANG-II-type-1 (AT1) receptors are involved incertain types of cardiovascular inflammation (Usuiet al., 2000). Furthermore, angiotensin-convertingenzyme (ACE) inhibitors have an anti-inflammatory effect (Delfraissy et al., 1984; Martin et al.,

1984; Rezkalla et al., 1990). We recently revealed
that ANG II and its receptors are involved in thedevelopment of fever (another example of an inflammatory response) both in rats (Watanabe et al.,1997, 2000; Miyoshi et al., 2003) and in mice
(Watanabe et al., 1999).
This review focuses on the role of ANG II and
its receptors in the development of febrile responses
in rodents.

Abbreviations: ACE, angiotensin-converting-enzyme; aCSF, artificial cerebrospinal fluid; ANG II, angiotensin II;
AT1, ANG II type 1; i.c.v., intracerebroventricular; i.h., intrahypothalamic; IL-1β, interleukin-1β; i.p., intraperitoneally; i.v., intravenous; LPS, lipopolysaccharide; PGE2, prostaglandin E2; PO/AH preoptic/anterior hypothalamic83

T. Watanabe et al.

LPS (2 µg/kg, i.v.) [8]Lisinopril (10 mg/kg, i.v.) + LPS (2 µg/kg, i.v.) [7]

(°C)
40

Body temperature

Dehydration + LPS
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IL-1β (2 µg/kg, i.v.) [7]
Lisinopril (10 mg/kg, i.v.) + IL-1β (2 µg/kg, i.v.) [6]

(°C)
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Body temperature

Dehydration + IL-1β
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Fig. 1. Effect of intravenous (i.v.) injection of lisinopril on lipopolysaccharide (LPS)- or interleukin-1β (IL-1β)induced fever in dehydrated rats. Changes (mean ± SEM) in body temperature (˚C) in dehydrated rats after i.v.
injection at time 0 of LPS (A: 2 µg/kg) or IL-1β (B: 2 µg/kg). Lisinopril (10 mg/kg) was administered i.v. immediately before the injection of LPS or IL-1β. [ ], number of subjects. Data from Watanabe et al. (2000).

the febrile response to pyrogenic cytokines is believed to be mediated by prostaglandin E (PGE),
acting within the brain as a final fever mediator(Blatteis and Sehic, 1997; Ushikubi et al., 2000).
We have reported that in rats, ANG II and its receptors contribute to the induction of fever not only
at its 1st step [namely, the LPS-induced productionof pyrogenic cytokines (Watanabe et al., 2000;

ANG II and Fever in Rats
It is widely accepted that once in the body, bacterial
endotoxin [or lipopolysaccharide (LPS)] stimulates
leukocytes to produce pyrogenic cytokines, such as
interleukin-1 (IL-1) or IL-6, leading to fever induction (Kluger, 1991; Dinarello, 1999). Furthermore,84

ANG II and fever in rodents

Miyoshi et al., 2003)] but also at its final step [namely, the action of PGE2 to cause fever (Watanabe etal., 1997)]. We should like to present our findings
below.

hepatic IL-1β mRNA at both 2 and 4 h after its injection, and this increase was reduced by treatment
with lisinopril (Fig. 2A), an effect that, by quantitative analysis, was revealed to be statistically significant (Fig. 2B) (Miyoshi et al., 2003). This result
suggested that ANG II contributes to the LPS-ANG II is involved in fever production inrats at its 1st step, the LPS-induced production of IL-1β
It is well known that a host develops a higher fever
under dehydrated conditions than under euhydrated
conditions. Indeed, in our hands, i.v. injection of agiven dose of LPS induced a fever that was significantly greater in dehydrated rats than in euhydrated
rats. However, dehydration had no effect on the
fever induced by i.v. injection of IL-1β (Watanabe
et al., 2000). These results suggested that the LPSinduced production of pyrogenic cytokines such as
IL-1β might be enhanced by dehydration. Furthermore, since the secretion of ANG II increases underdehydrated conditions it seemed possible that ANG
II might be involved in this enhanced production ofpyrogenic cytokines, and ultimately in enhancing
the fever seen in response to LPS. To test this possibility, we examined the effect of an angiotensinconverting-enzyme (ACE) inhibitor on febrile responses in dehydrated rats.
Figure 1 illustrates the effect of the ACE inhibitor lisinopril on the fever induced in dehydrated
rats by an i.v. injection of LPS (2 µg/kg) (Watanabe
et al., 2000). When lisinopril was given i.v. just before the LPS, the LPS-induced fever was significantly attenuated (Fig. 1A), indicating that ANG II
is indeed involved in LPS-induced fever in dehydrated rats. In contrast, the same inhibitor had noeffect on the fever induced by IL-1β itself (Fig. 1B),
suggesting that ANG II may act by contributing to
the LPS-induced production of pyrogenic cytokines,
such as IL-1β.
To test the above possibility, we then examined the effect of lisinopril on the expression of IL-1βmRNA in the liver of dehydrated rats given an i.v.
injection of LPS. Animals were sacrificed, the liver
quickly removed and its IL-1β mRNA examined by
Northern blot analysis. As shown in Fig. 2, LPS
induced a significant increase in the expression of

2h

A

4h

IL-1β

B

Saline + saline [6]Saline + LPS[6]Lisinopril + LPS [6](arbitrary unit)

S
LP
+
il
pr

no
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Li

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lin
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lin
Sa

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+

+

sa

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lin

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il

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si

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pr

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Sa

lin

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β-actin

Saline + saline [6]Saline + LPS[9]Lisinopril + LPS [8]P < 0.05120

IL-1β mRNA100

P < 0.05

80
60
40
20
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2h

4h

Fig. 2. Effect of i.v. injection of lisinopril on LPS-induced
increase in IL-1β mRNA expression in the liver in dehydrated rats. IL-1β mRNA expression in the liver of “Saline+ saline”, “Saline + LPS” and “Lisinopril + LPS” groups.
Lisinopril (20 mg/kg) or saline was administered i.v. 30
min before a single i.v. injection (at time 0) of LPS (2 µg/kg) or saline in dehydrated rats.
A: Autoradiograms showing IL-1β mRNA and β-actinmRNA bands in a representative animal from eachgroup at 2h and 4h after “time 0”.
B: Analysis of the density of the IL-1β mRNA bands ineach group. Mean values (± SEM) obtained for IL-1βmRNA in the liver are expressed in arbitrary units. For
each sample, the density of the IL-1β mRNA fraction
was normalized with respect to the β-actin density. [ ],number of subjects. Data from Miyoshi et al. (2003).

85

T. Watanabe et al.

Saline + saline [6]Saline + LPS[6]Lisinopril + LPS [6]induced induction of IL-1β at the mRNA level indehydrated rats.
Next we investigated the effect of lisinopril on
the production of IL-1β protein in the liver of dehydrated rats given an i.v. injection of LPS, the hepatic concentration of IL-1β being measured byenzyme-linked immunosorbent assay. The results
are depicted in Fig. 3. The LPS-induced increase in
the IL-1β protein concentration was significantly
attenuated by lisinopril at both 2 and 4 h after the
injection of LPS (Miyoshi et al., 2003). Furthermore, it should be mentioned that i.v. injection of
ANG type 1 (AT1) receptor antagonist reduced thisLPS-induced IL-1β response in the liver as well
(Miyoshi et al., 2003).
Taken together, the above results made it seem
likely that ANG II and the AT1 receptor are involved in the peripheral IL-1β production induced
in dehydrated rats by LPS.

(pg/100 µg protein)

Saline + saline [6]Saline + LPS[9]Lisinopril + LPS [8]P < 0.05
P < 0.05

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IL-1β

60

40

20

0

2h

4h

Fig. 3. Effect of i.v. injection of lisinopril on LPS-induced
increase in liver concentration of IL-1β protein in dehydrated rats. Changes (mean ± SEM) in liver concentrationof IL-1β in dehydrated rats 2 and 4 h after i.v. injection of
LPS (2 µg/kg). Lisinopril (20 mg/kg) or saline was administered i.v. 30 min before a single i.v. injection (at time 0) of
LPS (2 µg/kg) or saline. [ ], number of subjects. Data from
Miyoshi et al. (2003).

ANG II is also involved in fever production inrats at its final step, the action of PGE2 within
the brain to induce feverµg 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(Hogarty et al., 1992) in rats. Thus, since it seemedthat AT1 receptors are not involved in PGE2-induced
fever, even though they participate in stress-induced
hyperthermia, we hypothesized that the other ANG
receptor, the AT2 receptor, might contribute to thedevelopment of PGE2-induced fever. Indeed, we
found that when an AT2-receptor antagonist, CGP
42112A (20 µg), was administered i.c.v. just before
i.c.v. PGE2, the fever was significantly reduced(Watanabe et al., 1997). This result suggested thatAT2 receptors located somewhere in the brain contribute to the induction of fever by PGE2.
To try to determine where in the brain theseAT2 receptors might be situated, we gave intrahypothalamic (i.h.) injections of CGP 42112A andobserved their effects on fevers, because the rostral
hypothalamus is thought to be the site at which
PGE2 acts to induce fever. For these i.h. injections,a stainless-steel cannula was implanted into the preoptic/anterior hypothalamic (PO/AH) region on one
side at AP 1.8 mm, L 1.2 mm, and V 8.5 mm

Recently, we suggested that ANG II and its receptors within the brain participate in the developmentof one particular type of body-temperature increase,namely stress-induced hyperthermia (Saiki et al.,1997). Two types of ANG II receptors are present
within the brain, AT1 and AT2 receptors (Saavedra,
1994; Wright and Harding, 1994; Aguilera et al.,
1995; Watanabe et al., 1998) and we have shownthat the brain AT1 receptor is the one responsible
for the induction of restraint-stress-induced hyperthermia in rats (Saiki et al., 1997). We therefore
decided to investigate the effect of an intracerebroventricular (i.c.v.) injection of the AT1-receptor
antagonist losartan (60 µg) on the febrile responses
induced in rats by an i.c.v. injection of PGE2 (200ng), a final fever mediator (Blatteis and Sehic,
1997; Ushikubi et al., 2000). We postulated that
AT1 receptors play an important role in this type offever, too. Surprisingly, however, i.c.v. treatment
with losartan (60 µg) had no effect on the febrile
response induced by PGE2. This dose of losartan(60 µg) is actually rather high, because less than 1086

ANG II and fever in rodents

CGP42112A (5 µg, i.h.)aCSF + PGE 2 (100 ng, i.h.)
CGP42112A (2 µg, i.h.) + PGE 2 (100 ng, i.h.)

Body temperature

(˚C)
40

CGP42112A (5 µg, i.h.) + PGE 2 (100 ng, i.h.)

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36
–30

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30

60

90

120 (min)Time
Fig. 4. Effect of intrahypothalamic (i.h.) injection of CGP
42112A on prostaglandin E 2 (PGE 2 )-induced fever in rats.
Changes (mean ± SEM) in body temperature (˚C) in rats after i.h.
injection at time 0 of PGE2 (100 ng). CGP 42112A (2 µg, n = 11;
or 5 µg, n = 8) or aCSF (n = 9) was administered i.h. immediately
before the injection of PGE2. Also shown is the effect on resting
body temperature produced by CGP 42112A (5 µg i.h., n = 6)
given alone at time 0. Data from Watanabe et al. (1997).

aCSF+PGE 2 (25 ng, i.h.)
ANG II (25 ng, i.h.) + PGE 2 (25 ng, i.h.)

(˚C)
39

Body temperature[coordinates from the rat brain atlas of
Pellegrino et al. (1979)] under sodium
pentobarbitone anaesthesia (50 mg/kg, i.p.).
Figure 4 shows the effects of i.h. injections of CGP 42112A on the fever induced by PGE2 (Watanabe et al., 1997). In
artificial cerebrospinal fluid (aCSF)-treatedcontrols, injection of PGE2 (100 ng, i.h)resulted in a monophasic fever, the bodytemperature beginning to increase immediately and reaching peak at 25 min. This febrile response was attenuated by i.h. treatment with CGP42112A (2 and 5 µg) in adose-related manner, the effect being significant at P < 0.05 [for CGP42112A (5 µg) +PGE2, 0–40 min] (Fig. 4). CGP42112A (5µg, i.h.) given alone had no effect on resting
body temperature (Fig. 4).
These results suggest that AT 2 receptors in the rostral hypothalamus (PO/AH
region) are involved in PGE2-induced febrile responses in rats.
The question then arose as to whether
ANG II mediates or, on the other hand,modulates febrile responses through its
action on AT 2 receptors. To clarify thispoint, ANG II alone was administered into
the rostral hypothalamus to observe its effect on resting body temperature. The results showed that ANG II, given i.h. at 25 ng
or 5 µg, did not exert any significant effects
on body temperature in rats (Watanabe etal., 1997). It therefore seems unlikely that
ANG II mediates the induction of fever in
rats; rather, ANG II is more likely to modulate the fevers induced by other agents.
Having found that ANG II at a dose of 25 ng
i.h. had no effect on resting body temperature, we used this dose to investigate whether ANG II modulates the fever induced by
PGE2. As shown in Fig. 5, this dose of ANG
II, which had no effect on resting body temperature, enhanced the PGE2-induced fever(Watanabe et al., 1997), suggesting that
centrally acting ANG II modulates PGE2induced fever in rats.

38

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60

90

120 (min)Time

Fig. 5. Effect of i.h. injection of ANG II on PGE2-induced feverin rats. Changes (mean ± SEM) in body temperature (˚C) in rats
after i.h. injection at time 0 of PGE2 (25 ng). ANG II (25 ng, n =8) or aCSF (n = 8) was administered i.h. immediately before theinjection of PGE2. Data from Watanabe et al. (1997).

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(˚C)

Body temperature

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Control [8]AT2 -receptor-deficient [9]IL-1β (10 µg/kg, i.p.)

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300 (min)Time
Fig. 6. Febrile responses induced in control and AT2-receptor-deficient mice by intraperitoneal (i.p.) injection of IL1β. Changes (mean ± SEM) in body temperature in control and AT2-receptor-deficient mice after i.p. injection of IL1β (10 µg/kg). [ ], number of subjects. Data from Watanabe et al. (1999).

µg/2 µL perfusate/min) resulted in ANG II release(on average, 0.17 pg/2 µL perfusate/min; n = 3)
within the rat’s rostral hypothalamus (unpublishedobservations).

Finally, we investigated the effects of an i.h.
injection of an ACE inhibitor, lisinopril, on PGE2induced fever in rats. Lisinopril (5 or 10 µg, i.h.) oraCSF was given to rats 15 min before an injectionof PGE2 (100 ng, i.h.). The results showed thattreatment with lisinopril reduced the PGE2-induced
fever in a dose-related fashion (Watanabe et al.,1997). Lisinopril (10 µg, i.h.) given alone had nomarked effect on the resting body temperature.
Thus, inhibition of ANG II synthesis within the
rostral hypothalamus resulted in an attenuation of
PGE2-induced fever.
Taken together, our results suggest that in therat, hypothalamic ANG II, which is synthesized andreleased in response to PGE2, acts on AT2 receptors
located within the hypothalamus to facilitate PGE2induced fever. Interestingly, there are published reports indicating that AT2 receptors are present in the
rostral hypothalamus (Lenkei, et al., 1996; Lenkei,
et al., 1997). Moreover, using microdialysis (perfusion flow rate = 2 µL/min and recovery rate = 14.2%)
we recently found that i.h. perfusion with PGE2 (2ANG II and Fever in Mice
Recently, 2 laboratories developed mice deficientin AT2 receptors that showed increased pressor
responses to ANG II and a lower than normal bodytemperature (Hein et al., 1995; Ichiki et al., 1995).
These mice also exhibit attenuated exploratory behavior and reduced spontaneous movements, suggesting that endogenous ANG II and AT2 receptors
regulate brain functions. We administered IL-1β
intraperitoneally (i.p.) to AT2-receptor-deficient
mice to allow us to compare the febrile response insuch mice with that in wild-type mice. As shown in
Fig. 6, in the controls a single injection of IL-1β (10µg/kg, i.p.) resulted in a biphasic fever which began
after 5 min and reached its 1st peak at 15 to 20 min
88ANG II and fever in rodents(Watanabe et al., 1999). The 2nd peak occurred ataround 60 min. The 1st phase involves an injectionstress-induced hyperthermia, while the 2nd phase isa true IL-1β fever. This IL-1β fever was suppressedin the AT2-receptor-deficient mice, the effect being
significant at P < 0.05 (25–180 min), while there
was no difference in the 1st phase of thehyperthermia between the 2 groups of mice. The
body temperature of the mutant mice was similar tothat of the controls from 150 min onwards.
These results suggest that in mice, the pathway
distal to the point at which IL-1β acts involves anaction of ANG II on AT2 receptors. Since in rats central injection of an AT2-receptor antagonist attenuates PGE2-induced fever [see above (Watanabe etal., 1997)], it is likely that the brain AT2 receptor isimportant in the induction of PGE2-induced fever inmice as well in rats. However, it should be noted in
the above results that an attenuation of the IL-1β
fever was observed only during the early stage ofthe hyperthermia (10–180 min). Therefore, it may
be that the AT2 receptor is just one of a number offactors contributing to IL-1β fever, and that its important role is performed mainly during the risingphase of this fever.

It is widely accepted that PGE2 acts within the
rostral hypothalamus to induce fever, as a final
mediator (Blatteis and Sehic, 1997; Ushikubi et al.,2000). We found that i.h. injection of either an
AT2-receptor antagonist or an ACE inhibitor inhibited the fever induced by an i.h. injection of PGE2.
Furthermore, ANG II given i.h., which had no effect on the resting body temperature, facilitated
PGE2-induced fever (Watanabe et al., 1997). These
results suggest that hypothalamic ANG II, following its synthesis and release in response to PGE2,
acts on AT2 receptors in the rat hypothalamus tofacilitate PGE2-induced fever.
Finally, when we gave a single i.p. injection of
IL-1β to AT2-receptor-deficient mice we found that
the IL-1β-induced fever was significantly weaker
than in the wild-type mice, suggesting that the brain
AT2 receptor is involved in the development of suchfever in mice as well.
Taken together, the observations reviewed
here make it seem likely that ANG II contributes tothe development of fever by acting at both the 1st
and final steps in the pathway for fever-induction inrodents.

Acknowledgments: The authors gratefully acknowledge 3
collaborators who contributed to the studies described here,
Dr. Yukio Saiki, Dr. Yoshiyuki Sakata and Dr. Katsumi
Nagata. We also thank Dr. R. Timms for his critical readingof the English manuscript. We are grateful to Otsuka Pharmaceutical and Dupon Merk Co. Ltd. for the supply of human recombinant IL-1β and losartan, respectively.
These studies were partly supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Science, and Culture, Japan.

Concluding Remarks
In this mini-review, we have focussed on the role of
ANG II in the development of fever in rats andmice.
We have shown that an i.v. injection of LPS
induces a fever that is significantly greater in“dehydrated” than in “euhydrated” rats (Morimoto
et al., 1986; Watanabe et al., 1997). We have suggested i) that the LPS-induced production of pyrogenic cytokines such as IL-1β might be enhanced
by dehydration and ii) that ANG II is involved inthis enhanced production of pyrogenic cytokines,
and ultimately in enhancing the fever seen in response to LPS. Indeed, an ACE inhibitor inhibitedthe LPS-induced production of hepatic IL-1β, aswell as the fever, in dehydrated rats (Watanabe etal., 2000; Miyoshi et al., 2003).

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Received and accepted September 19, 2003
Corresponding author: Tatsuo Watanabe, MD, PhD

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