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in pregnant rats
Departments of 1 Physiology and Biophysics and 2 Pathology and Clinical Neurosciences, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada T2N 4N1
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Rats have an attenuated febrile
response to endogenous pyrogen near the term of pregnancy. Given the
fundamental role of E-series prostaglandins (PGEs) in mediating the
febrile response to blood-borne endogenous pyrogen, the present
experiments were carried out to determine whether PGEs increase in the
area surrounding the organum vasculosum laminae terminalis (peri-OVLT)
of near-term pregnant (P) rats as in nonpregnant (NP) rats after
intravenous (iv) administration of recombinant rat interleukin-1
(rrIL-1). Core temperature was measured by telemetry and peri-OVLT
interstitial fluid was sampled in 12 NP and 12 P chronically
instrumented, Sprague-Dawley rats by microdialysis for determination of
total PGEs by radioimmunoassay. Basal core temperatures were higher in
NP compared with P rats (NP 37.9°C ± 0.5, P 36.9°C ± 0.4; P < 0.05), but basal peri-OVLT PGEs were similar
in both groups (NP 260 ± 153 pg/ml, P 278 ± 177 pg/ml;
P =not significant). Intravenous administration of rrIL-1
to NP rats produced a significant increase in core temperature with a
latency, magnitude, and duration of 10 min, 0.87°C, and at least 170 min, respectively; peri-OVLT PGEs were increased significantly by 30 min and averaged 270% above basal levels throughout the experiment. In
P rats, however, neither core temperature nor peri-OVLT PGEs increased
significantly after iv administration of rrIL-1. Intravenous
administration of vehicle did not significantly alter core temperature
or peri-OVLT PGEs in either group of rats. Thus peri-OVLT PGEs do not
increase in P rats as they do in NP rats after iv administration of
rrIL-1. The mechanism of this interesting component of the maternal
adaptation to pregnancy, which likely plays a major role in mediating
the attenuated febrile response to endogenous pyrogen near the term of
pregnancy, warrants further investigation.
cytokine; endogenous pyrogen; exogenous pyrogen; interleukin; microdialysis; organum vasculosum laminae terminalis
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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FEVER, A HALLMARK OF
the body's response to infection, is a highly regulated process
(54) involving the synthesis and release of both pyrogens
and antipyretics (14). After exposure to a blood-borne
exogenous pyrogen, such as the cell wall of gram-negative bacteria
(i.e., lipopolysaccharide), cells of the immune system synthesize and
secrete endogenous pyrogens such as the cytokine interleulin (IL)-1
(17). Classically, IL-1 is thought to act within the
organum vasculosum laminae terminalis (OVLT), a circumventricular organ
in close proximity to the preoptic area of the anterior hypothalamus,
to evoke the synthesis and release of E-series prostaglandins (PGEs)
that serve to activate heat-producing and heat-conserving mechanisms to
increase core temperature (30, 55). Endogenous antipyretics [e.g., arginine vasopressin (15, 16)] are
also released by the body during the course of the febrile response and
effectively limit the magnitude and duration of the core temperature response.
Over 20 years ago, Kasting et al. (29) reported that fever
in response to exogenous pyrogen (i.e., lipopolysaccharide from Salmonella abortus equi) was suppressed in sheep near the
term of pregnancy. Although the mechanism and consequences of
this interesting thermoregulatory component of the maternal adaptation to pregnancy remain largely unknown, it has now been shown to occur in
a number of species, including rats (38). Moreover, Simrose and Fewell (52) have shown that the febrile
response to IL-1 is absent in rats near the term of pregnancy. Given
the fundamental role of PGEs in mediating the febrile response to blood-borne endogenous pyrogen (55), the present
experiments were carried out to determine whether PGEs increase in the
interstitial fluid surrounding the OVLT of nonpregnant and pregnant
rats as in male rats (31) after intravenous (iv)
administration of recombinant rat IL-1 (rrIL-1). Specifically,
our experiments were designed to test the hypothesis that pregnancy
impairs the synthesis and release of PGEs into the interstitial fluid
of the peri-OVLT region after iv administration of rrIL-1.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were carried out on 12 nonpregnant and 12 pregnant Sprague-Dawley rats (Charles River Laboratories) undergoing their first pregnancy. The rats were housed individually in Plexiglas cages containing Aspen-Chip Laboratory bedding (Northeastern Products) in a humidity-controlled environmental chamber at an ambient temperature of 22 ± 1°C in a 12:12-h light-dark cycle (lights on at 0700) and were handled several times before an experiment to familiarize the animal with the investigator. All animals had continuous access to food (Lab Diet 5001) and tap water.
Surgical peparation.
Five days before an experiment, each rat was anesthetized by an
intraperitoneal injection of pentobarbital sodium (50 mg/kg). By means
of a paramedian laparotomy, a free-floating battery-operated biotelemetry device (VM-FH, Mini-Mitter) was inserted into the peritoneal cavity for later measurement of core temperature. In addition, a sterile and endotoxin-free catheter (PhysioCath, Data Sciences International) was inserted into the superior vena cava via
the right jugular vein for administration of rrIL-1. The catheter
was then tunneled under the skin and exteriorized on the dorsal
scapular area. Between surgery and an experiment, the catheter was
filled with a sterile heparin solution (1,000 U/ml), and a 25-gauge
stainless steel wire was inserted into the end to seal the catheter.
Conditions of observations. During an experiment, each animal was studied in a BAS containment system for awake animals (MD-1575); key components of this system include a round-bottomed containment bowl (MD-1500), a counterbalanced arm (MD-1501), a liquid swivel (MD-1505), a tether assembly with vial support (MD-1509), and a system table (MD-1504) that accommodates a variable-speed infusion pump (CMA-100). This system allows in vivo sampling experiments to be carried out on conscious animals with minimal handling or restraint stress in that the subjects have some freedom of movement, comfortable bedding, and free access to food and water during an experiment. Ambient temperature was maintained at 22 ± 1°C, and each containment bowl was placed over a platform antenna (PhysioTel CTR 86, Data Sciences International) that received the output frequency (Hz) from the biotelemetry device; each platform antenna was interfaced with a peripheral processor (Dataquest iv; Data Sciences International) for determination of core temperature.
Experimental protocol.
Twelve nonpregnant and 12 pregnant rats were allocated to two
experimental groups on the basis of whether they received an iv
injection of rrIL-1 (nonpregnant n = 6; pregnant
n = 7) or vehicle (nonpregnant n = 6;
pregnant n = 5), and each animal was studied only once.
Pregnant animals were studied on day 19, 20, or
21 of gestation (term ~22 days). All experiments were
carried out during the light cycle and began between 1000 and 1100 to avoid any circadian effects on the measured variables.
or
vehicle was injected via the venous catheter and dialysate samples were
collected over 30-min intervals for 180 min. Dialysate samples were
stored at 
70°C until they were analyzed for total PGE content with
use of a radioimmunoassay. Core temperature was recorded throughout the
experiment at 10-min intervals.
After an experiment, the rat was anesthetized with pentobarbital
sodium. The chest was then opened, and the vascular system was perfused
through the heart with normal saline, followed by 10% buffered
formalin to fix the brain tissue. The location of the tip of the
dialysis probe was then verified histologically by R. N. Auer
(hematoxylin and eosin-stained 6-µm sections) in 12 randomly selected
rats out of the 24 studied to lie within the peri-OVLT region (i.e.,
within 1 mm of the OVLT).
rrIL-1.
rrIL-1 was purchased from R & D Systems as a lyophilized sample from
a sterile, filtered solution in phosphate-buffered saline, containing
50 µg of bovine serum albumin per 1 µg of cytokine. The sample was
reconstituted by adding sterile phosphate-buffered saline containing
1% bovine serum albumin to the vial to make a stock solution of 10 µg/ml. This solution was divided into ~100-µl aliquots and stored
at 70°C in sterile plastic vials. On the day of the experiment, a
sample of stock solution was thawed and diluted to the appropriate dose
in phosphate-buffered saline containing 1% bovine serum albumin to
make a total injected volume of 200 µl. The dose of rrIL-1 (i.e.,
0.2 µg/kg) used in our experiments was the dose that produced a
half-maximal core temperature response in experimental series testing
doses from 0.1 to 2.0 µg/kg in nonpregnant animals (22).
In previous experimental series testing doses of IL-1 from 0 to 6.4 µg/kg in near-term pregnant animals, our laboratory did not observe
significant increases in core temperature (60).
Vehicle was phosphate-buffered saline containing 1% bovine serum
albumin, and all injections were followed by 0.2 ml of sterile saline
to flush the catheter.
PGE radioimmunoassay. Radioimmunoassay of PGE in microdialysates was performed according to the method of Van Orden et al. (57) with minor modifications as follows. Microdialysates were not subjected to chromatography but were added directly to the assay tubes, and PGE2 [125I]iodotyrosine methyl ester was used in place of tritiated PGE2. Sensitivity, defined as the least amount of PGE distinguished from 0 at the 95% confidence level, was 1.0 pg. Specificity of the PGE antibody as well as intra- and interassay coefficient of variations have been previously reported (57).
Statistical analysis.
Statistical analysis was carried out by using a three-factor analysis
of variance for repeated measures followed by a Newman-Keuls multiple-comparison test to determine whether state (pregnant or
nonpregnant), injectate (vehicle or rrlL-1), or time influenced core
temperature or PGE levels. In addition, a two-factor ANOVA followed by
a Newman-Keuls multiple-comparison test was carried out to determine
whether state or injectate influenced the fever index (15)
expressed as area under the core temperature-time curve for the 3 h after iv administration of vehicle or rrlL-1. All results are
presented as means ± SD; P < 0.05 was considered to be of statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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As we have previously reported (20, 23), basal core
temperatures were significantly (P < 0.05) higher in
nonpregnant rats (37.9 ± 0.5°C) compared with near-term
pregnant rats (36.9 ± 0.4°C). The iv administration of
rrIL-1 to nonpregnant rats produced a significant increase in core
temperature with a latency, magnitude, and duration of 10 min,
0.87°C, and at least 170 min, respectively (Figs.
1 and 2).
There were no significant effects of iv administration of rrIL-1 on
core temperature in near-term pregnant rats or of iv administration of
vehicle in either group of rats.
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Basal PGE levels were similar (not significant) in dialysate fractions
collected from nonpregnant (260 ± 153 pg/ml) and pregnant (278 ± 177 pg/ml) rats. PGE levels in the interstitial fluid
surrounding the OVLT increased significantly after iv administration of
rrIL-1 in nonpregnant rats, averaging 270% of control values
throughout the experiment (Fig. 3). PGE
levels did not change significantly after iv administration of
rrIL-1 in pregnant rats or after administration of vehicle in either
group of rats.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our experiments provide new information about potential mechanisms
of the attenuated febrile response to endogenous pyrogen near the term
of pregnancy in rats (52). Novel findings were that iv
administration of rrIL-1 produced significant increases in peri-OVLT
PGEs and core temperature in nonpregnant rats but not in near-term
pregnant rats. Thus our data support the hypothesis that pregnancy
impairs the synthesis and release of PGEs into the interstitial fluid
of the peri-OVLT region after iv administration of rrIL-1. The
mechanism of this interesting component of the maternal adaptation to
pregnancy, which likely plays a major role in mediating the attenuated
febrile response to endogenous pyrogen near the term of pregnancy, is
currently unknown.
As we have previously observed and reported (20, 23), basal core temperatures were significantly higher in nonpregnant rats compared with near-term pregnant rats. The "regulated" decrease in core temperature near the term of pregnancy most likely results from the hormonal changes that occur at this time of gestation in rats. For example, Yoshinaga et al. (61) showed that ovarian venous levels of estrogen are low during the first two-thirds of gestation, increase slowly from day 14 or 15 of gestation toward term, and then increase precipitously from day 20 of gestation to the time of parturition. To the contrary, ovarian venous and systemic levels of progesterone increase slowly during the first two-thirds of gestation, decrease slowly from day 14 or 15 of gestation toward term, and then decrease precipitously from day 19 or 20 of gestation to the time of parturition (27, 43). Given that administration of progesterone or estradiol raises metabolic rate and core temperature in ovariectomized rats (34, 37), progesterone appears to be the most likely candidate for mediating the changes in basal core temperature near the term of pregnancy in this species. Progesterone has long been known to have thermogenic effects (25, 47) and recently has been shown to influence firing patterns of preoptic thermosensitive neurons (46). This postulate requires further investigation.
In 1948, Beeson (3) identified endogenous pyrogen as a
fever-inducing substance produced and released by circulating
leukocytes and fixed macrophages in response to exogenous pyrogens
(i.e., bacterial endotoxin, lipopolysaccharide). This substance was
later renamed IL-1, and its release as well as the release of other endogenous pyrogens, such as IL-6 and tumor necrosis factor-
, constitutes an essential step in the genesis of fever after exposure to
exogenous pyrogens (17). Classically, IL-1 is thought to act within the OVLT to evoke the synthesis and release of PGEs that
serve to activate heat-producing and heat-conserving mechanisms to
increase core temperature (30, 55).
It was Milton and Wendlandt (41) who first presented
evidence that prostaglandins play a role in fever when they reported that intracerebroventricular (icv) administration of PGE1
in conscious cats elicited an increase in core temperature along with
shivering, piloerection, and peripheral vasoconstriction and with the
animals assuming a "curled-up" position; comparable results were
later obtained after icv administration of PGE2
(42). Similar observations have been made in rats
(36, 50), and numerous studies have shown that
prostaglandins are released into the cerebrospinal fluid (4, 12,
48) during pyrogen-induced fevers. Furthermore, congenital
absence of the PGE-receptor subtype EP3 impairs the febrile
response to exogenous and endogenous pyrogens in mice (56). Moreover, Komaki et al. (31)
showed that iv injection of IL-1 causes increased levels of
PGE2 in the interstitial fluid of the OVLT and the medial
preoptic area of the hypothalamus in rats. This is relevant to
febrigenesis because Scammell et al. (51) recently showed
that neuroanatomic sites clustered along the ventromedial aspect of the
preoptic area just anterior to the OVLT are the most pyrogenic in
response to microinjection of PGE2; this area has a high
concentration of PGE2-binding sites (39, 59).
We have previously shown that pregnant as well as nonpregnant rats
activate both behavioral and autonomic thermoregulatory effectors to
increase core temperature after icv injection of the pyrogen
PGE1 (19); the duration of activation,
however, is abbreviated in pregnant compared with nonpregnant rats, and this appears to limit the magnitude and duration of the febrile response. Subsequent experiments have shown that near-term pregnant rats develop "normal" core temperature responses to an icv
injection of PGE1 (21) when it follows an icv
injection of a vasopressin V1-receptor antagonist. This
suggests that, if exposure to exogenous or endogenous pyrogen elicits a
normal PGE response in near-term pregnant animals, arginine vasopressin
acting as an endogenous antipyretic would serve to limit the magnitude
and duration of the core temperature response. Interestingly, icv
injection of a vasopressin V1-receptor antagonist does not
"normalize" the core temperature response of near-term pregnant
rats to an iv injection of rrIL-1 (22). This led us to
speculate, as demonstrated in the present study, that iv administration
of rrIL-1 does not elicit a normal PGE response in pregnant animals
as it does in nonpregnant animals.
Although our present experiments were not designed to investigate the
mechanism of the attenuated PGE response in near-term pregnant rats
after exposure to blood-borne pyrogen, there are at least three
possibilities. First, it is possible that blood-borne rrIL-1 does
not elicit a normal end-mediator response because there is an
alteration in the number or properties of cytokine receptors near the
term of pregnancy. Alternatively, there may be an increase in the
circulating levels of IL-1-receptor antagonist that competes with
IL-1 for occupancy of type I and type II IL receptors on a variety
of cells (2). This has been shown to occur in
humans near the term of pregnancy (49). Second, it is
possible that corticosterone mediates the altered PGE response in
near-term pregnant rats. Corticosterone, which modulates fever after
exposure to lipopolysaccharide (40, 45), is elevated near
the term of pregnancy in rats (18, 53). Glucocorticoids (e.g., corticosterone) are antipyretic (10, 13) and are
known to stimulate the production of lipocortin-1, a calcium-dependent phospholipid-binding protein that inhibits phospholipase
A2. Phospholipase A2 is responsible for
mobilization of arachidonic acid, a precursor of the eicosanoids,
including prostaglandins, from membrane phospholipids (24). Third, it is possible that cyclooxygenase-2 (COX-2),
an inducible enzyme that plays a major role in prostaglandin production during inflammation, is downregulated by the increased glucocorticoids levels that occur near the term of pregnancy in rats (58).
In fact, selective COX-2 inhibitors suppress the febrile response produced by intraperitoneal as well as icv injections of
lipopolysaccharide, IL-1, and tumor necrosis factor-
(7-9). Furthermore, COX-2(/) mice do not develop
fever after intraperitoneal administration of lipopolysaccharide
(35). These possibilities warrant further investigation.
Regardless of the mechanism of the altered PGE response to pyrogen near term of pregnancy in rats, what are the possible physiological consequences for the fetus of an attenuated maternal febrile response to blood-borne pyrogen near the term of gestation? From the standpoint of oxygen supply and demand, it may be advantageous to the fetus for the mother not to develop fever for several reasons. One reason is that febrigenesis may cause circulatory adjustments such that blood flow from internal body organs, including the uterus and placenta (5), is directed toward thermogenic organs (e.g., brown adipose tissue). The resulting decrease in uteroplacental blood flow could compromise placental gas exchange with a resulting decrease in fetal oxygen supply (11). Another reason is that fetal core temperature, which is normally 0.4-0.8°C higher than maternal body temperature (1), increases in parallel (1, 26) or exceeds (32) the rise in maternal core temperature during febrigenesis with a resulting increase in oxygen demand secondary to the temperature coefficient of metabolism (i.e., Q10). Given that the Q10 in humans is ~2.3 (28), the metabolic rate increases ~10% for each 1°C increase in core temperature. A moderate increase in core temperature during the latter part of gestation may be detrimental to the fetus not only by increasing oxygen demand but also by causing a rightward shift of the oxyhemoglobin dissociation curve, thereby decreasing oxygen affinity and oxygen saturation. Studies in primates have shown that hyperthermia in the absence of infection is associated directly with the development of fetal hypoxia, metabolic acidosis, and hypotension (44). Furthermore, in conditions where fetal oxygen availability is severely limited (e.g., asphyxia during birth), an increase in core temperature may exacerbate neuronal injury (6, 33) and increase perinatal morbidity and mortality.
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ACKNOWLEDGEMENTS |
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We thank Dr. Francine G. Smith for critical review of this manuscript and Dr. Dubravka Rakic for technical assistance.
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FOOTNOTES |
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This study was supported by the Canadian Institutes of Health Research.
Address for reprint requests and other correspondence: J. E. Fewell, Heritage Medical Research Bldg., 206, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1 (E-mail fewell{at}ucalgary.ca).
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/japplphysiol.01036.2001
Received 12 October 2001; accepted in final form 6 April 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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