Vol. 282, Issue 6, R1718-R1729, June 2002
Arterial baroreceptors mediate the inhibitory effect of acute
increases in arterial blood pressure on thirst
Sean D.
Stocker,
Edward M.
Stricker, and
Alan F.
Sved
Department of Neuroscience, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
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ABSTRACT |
The present study sought to
determine whether arterial baroreceptor afferents mediate the
inhibitory effect of an acute increase in arterial blood pressure (AP)
on thirst stimulated by systemically administered ANG II or by
hyperosmolality. Approximately 2 wk after sinoaortic denervation, one
of four doses of ANG II (10, 40, 100, or 250 ng · kg
1 · min1) was
infused intravenously in control and complete sinoaortic-denervated (SAD) rats. Complete SAD rats ingested more water than control rats
when infused with 40, 100, or 250 ng · kg1 · min1 ANG II.
Furthermore, complete SAD rats displayed significantly shorter
latencies to drink compared with control rats. In a separate group of
rats, drinking behavior was stimulated by increases in plasma
osmolality, and mean AP was raised by an infusion of phenylephrine (PE). The infusion of PE significantly reduced water intake and lengthened the latencies to drink in control rats but not in complete SAD rats. In all experiments, drinking behavior of rats that were subjected to sinoaortic denervation surgery but had residual
baroreceptor reflex function (partial SAD rats) was similar to that of
control rats. Thus it appears that arterial baroreceptor afferents
mediate the inhibitory effect of an acute increase in AP on thirst
stimulated by ANG II or hyperosmolality.
water intake; angiotensin II; hyperosmolality
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INTRODUCTION |
ACCUMULATING EVIDENCE
INDICATES that an acute increase in arterial blood pressure (AP)
inhibits thirst. Initial observations by Evered and colleagues
(3, 4, 17) demonstrated that cumulative water intakes in
rats were greater when the increase in AP evoked by an intravenous
infusion of ANG II was prevented by cotreatment with one of three
vasodilators [isoproterenol, diazoxide (DZX), or minoxidil]. With
each dose of ANG II tested and all three vasodilators used, attenuation
of the ANG II-induced increase in AP resulted in a greater cumulative
water intake (3, 4, 17). Similar observations have been
reported in dogs (13). Recently, we confirmed those
findings and also demonstrated that an acute increase in AP inhibits
drinking behavior stimulated by hyperosmolality or hypovolemia in rats
(21). With all three stimuli for thirst, an acute increase
in AP resulted in a reduction of water intake and a longer latency to
drink. Furthermore, this inhibitory effect of an increase in AP on
thirst appeared to be graded; small increases in AP resulted in
small reductions in water intake and longer latencies to drink, whereas
large increases in AP resulted in larger reductions in water intake and
even longer latencies to drink (21).
The primary way in which the central nervous system detects acute
perturbations in AP is through an afferent signal arising from stretch
receptors located on the vessel walls of the aortic arch and carotid
sinus (arterial baroreceptors). Previous studies attempting to remove
arterial baroreceptor afferents have not observed potentiated water
intakes evoked by peripherally administered ANG II (10,
16). However, it is not clear whether the baroreceptor afferents
of the animals in these studies were completely eliminated, as
discussed previously (21). On the other hand, complete
elimination of both arterial and cardiopulmonary baroreceptor
afferents, by surgical denervation in dogs (11) or
electrolytic lesions of the nucleus tractus solitarius (NTS) in rats
(18), results in greater water intake and shorter latency
to drink during an intravenous infusion of pressor doses of ANG II.
Therefore, the inhibitory effect of an acute increase in AP may be
mediated by both cardiopulmonary and arterial baroreceptors. However,
because no study has convincingly evaluated the contribution of
arterial baroreceptors to the AP-evoked inhibition of thirst stimulated
by peripherally administered ANG II, it is unclear whether one or both
types of afferents mediate this inhibition. Therefore, we sought to
reinvestigate whether complete removal of arterial baroreceptor
afferents eliminates the inhibition of drinking behavior resulting from
an acute increase in AP.
In the present experiments, sinoaortic-denervated (SAD) rats plus
nonsurgical controls were infused intravenously with several doses of
ANG II. If arterial baroreceptors mediate the inhibition of drinking
behavior during an acute increase in AP, then complete SAD rats should
drink sooner and ingest more water compared with weight-matched control
rats during an intravenous infusion of pressor doses of ANG II. In
addition, we sought to determine whether complete removal of arterial
baroreceptor afferents would eliminate the inhibition of thirst
observed during increases in AP when drinking behavior was stimulated
by hyperosmolality. Thus SAD rats and weight-matched controls were
infused with hypertonic saline (HS) to raise plasma osmolality
(Posmol), and AP was raised by an infusion of phenylephrine
(PE). In all experiments, partial SAD rats also were studied to
determine whether drinking responses of these rats were affected by an
increase in AP, like control rats.
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METHODS |
Animals.
Adult male Sprague-Dawley rats (Zivic Laboratories, Zelienople, PA)
were individually housed in a temperature-controlled room (22-23°C) with a 12:12-h light-dark cycle (lights on at 8:00
AM). Tap water and Purina Laboratory Chow (no. 5001) were available ad
libitum except where noted. All experiments began between 10:00 AM and
2:00 PM. At least 24 h before baroreflex testing, catheters were
implanted in the left femoral artery (Silastic or Microrenthane tubing;
Braintree Scientific) and vein (PV-3 tubing) using halothane as
anesthesia (2-3% in 100% O2). All catheters were
tunneled subcutaneously to exit between the scapulae and were filled
with heparinized saline (arterial, 1,000 U/ml; venous, 40 U/ml). Rats
were fitted with an infusion harness (Harvard Apparatus) that allowed
the catheters to pass outside the cage while protected by a steel spring.
At least 1 h before experiments began, rats were weighed and
returned to wire mesh cages with urine collection funnels attached to
the bottom. Food was removed, and a 50-ml burette containing tap water
was placed on the cage except where noted. AP was recorded by
connecting the arterial line to a Statham pressure transducer (Grass
Instruments, Quincy, MA) and a polygraph chart recorder (model 7; Grass
Instruments). The pulsatile AP signal was electronically filtered to
obtain mean AP (MAP). Heart rate (HR) was obtained through a tachograph
(model 7P44; Grass Instruments) triggered by the pulsatile AP. During
drinking experiments, MAP and HR values for each time point were
computed as an average of three values taken 10 s apart. Because
the act of drinking has been reported to increase MAP and HR
(8), MAP and HR values were not taken during a drinking
bout, but values were collected at the closest minute to the drinking bout.
Sinoaortic denervation.
Approximately 2 wk before baroreflex testing and initiation of drinking
experiments, sinoaortic denervation was performed using halothane as
anesthesia (2-3% in 100% O2), as described previously (12, 19). Briefly, the superior cervical
ganglion was removed, and the superior laryngeal nerve was sectioned at its junction with the vagus nerve. The common carotid artery, carotid
bifurcation, and internal and external carotid arteries were stripped
of neural and connective tissue and swabbed with 10% phenol in
ethanol. After surgery, rats were injected with either hexamethonium
(30 mg/kg sc) or atropine (0.1 mg/kg sc) two times daily for 2 days and
with antibiotic (Dual-Cillin; 30,000 units im). Because water intake
usually decreases after sinoaortic denervation, rats also were given
daily injections of isotonic saline (SLN, 15 ml sc) until spontaneous
drinking resumed.
Baroreflex testing.
The completeness of the sinoaortic denervation was assessed by
observing changes in HR in response to intravenous bolus injections of
PE (4 µg/kg) and sodium nitroprusside (SNP; 4 µg/kg), as described previously (19). To verify that cardiac afferents were not
affected by these surgical denervations, rats were tested additionally for MAP and HR responses to the 5-HT3 5-hydroxytryptamine
agonist phenyl biguanide (PBG; 25 µg/kg iv). All baroreflex testing
was performed in awake, freely-moving rats. Each rat was tested at least three times for AP and HR responses to PE, SNP, and PBG, and peak
changes in each variable were averaged across trials. A denervation was
considered to be complete when the change in HR in response to PE and
SNP was 0 beats/min; such rats will be referred to as "complete SAD
rats." Rats that underwent these surgical denervations but still had
residual baroreceptor reflex function will be referred to as "partial
SAD rats." In addition, "control" rats consisted of
weight-matched rats that did not undergo sinoaortic denervation
surgery. Baseline MAP was calculated as an average of values taken
every 20 s for 5 min immediately before baroreflex testing.
Lability of MAP was calculated as the standard deviation of the mean.
Effect of sinoaortic denervation on drinking behavior during an
infusion of ANG II.
After a 20-min baseline recording of MAP and HR, complete SAD
(n = 5), partial SAD (n = 5-10),
and control (n = 8) rats were infused intravenously
with one of four doses of ANG II (10, 40, 100, or 250 ng · kg1 · min1; 25 µl/min) for 60 min using an infusion pump (model A-99; Razel). Experiments were performed every other day, and the infusion dose of
ANG II was randomized. In initial experiments, two complete SAD rats
were tested for drinking responses to only 10 and 100 ng · kg1 · min1 ANG II. The
results from these rats were combined with the results from five other
complete SAD rats infused with 10, 40, 100, and 250 ng · kg1 · min1 ANG II.
Cumulative water intakes (±0.5 ml) were monitored every 15 min during
the 60-min test. Latencies from the initiation of the ANG II infusion
to the first lick on the water tube also were noted. To assess whether
large changes in urinary output might underlie any observed changes in
drinking behavior, urine outputs (±0.1 ml) were monitored during the
60-min test and then analyzed for Na+ and K+
concentrations (System E2A Electrolyte Analyzer; Beckman Instruments, Brea, CA).
Effect of intravenous infusions of ANG II on plasma ANG II
levels.
To determine the plasma ANG II levels resulting from the infusion of
ANG II, a separate group of control rats (n = 8) was infused with ANG II (10, 40, 100, and 250 ng · kg1 · min1; 25 µl/min). In addition, a subset (n = 4) of complete
SAD rats used in the above drinking studies was infused with 40 and 100 ng · kg1 · min1 ANG II for
determination of plasma ANG II levels. In each animal, blood samples
(0.5 ml) were collected from the arterial catheter into microcentrifuge
tubes containing 3 mM EDTA (15 µl) and 20 mM 1,10-phenanthroline (45 µl) at baseline and at 3, 15, and 45 min after the initiation of the
ANG II infusion. Samples were centrifuged immediately (10,000 g, 1 min), and the plasma was stored at 
80°C until ANG
II levels were determined by RIA, as described previously
(22). In this and subsequent experiments, the first blood
sample was replaced with an equal volume of SLN injected intravenously,
whereas subsequent samples were replaced with red blood cells
from the previous sample resuspended in heparinized saline (40 U/ml).
To compare the plasma ANG II levels resulting from the intravenous
infusions of ANG II with plasma ANG II levels associated with other
treatments known to stimulate thirst, separate groups of rats received
one of several treatments. Some rats were water deprived for 0 (n = 6), 24 (n = 6), or 48 (n = 8) h and then decapitated; trunk blood was
collected in microcentrifuge tubes containing 10 mM EDTA and 20 mM
1,10-phenanthroline. Other rats (n = 5), with femoral
arterial and venous catheters inserted 2 days previously, were infused
with HS (1 M NaCl; 2 ml/h iv) for 60 min. Blood samples (1.5 ml) were
collected in microcentrifuge tubes as described above at baseline and
60 min after the onset of the infusion. An additional group of rats
with femoral arterial and venous catheters received an injection of the
arteriolar vasodilator DZX (25 mg/kg iv; n = 8), and
blood samples were collected 30 min later. All samples were centrifuged
(10,000 g, 1 min) and stored at 80°C until plasma ANG II
levels were determined by RIA.
Effects of sinoaortic denervation on the AP-evoked inhibition of
drinking behavior during increases in Posmol.
One hour before experiments, food and water were removed from the
cages. After a 20-min baseline recording of MAP and HR, rats were
infused with HS (1 M NaCl, 2 ml/h) for 2 h. At the end of the 2-h
period, the infusions were switched either to PE (4 µg · kg1 · min1), to
increase AP, or to SLN (1.5 ml/h) for the next 90 min. Control (n = 8), partial SAD (n = 5), and
complete SAD (n = 5) rats were subjected to both the PE
and SLN protocols separated by 3 days, and the order was randomized.
Water access was allowed 10 min after the onset of the SLN or PE
infusions. When the water bottle was returned to the cage, a few drops
of water were placed on each rat's snout to make it aware that water
was accessible again. Cumulative water intakes (±0.5 ml) were
monitored every 15 min, and latencies to drink also were recorded.
Urine outputs (±0.1 ml) were monitored before and every 15 min after
access to water during the test and later analyzed for Na+
and K+ concentrations as described previously.
Additionally, blood samples (0.3 ml) were collected from the arterial
line in microcentrifuge tubes containing heparin (10,000 U/ml, 0.2 µl) 10 min before the infusion of 1 M NaCl, just before water access,
and 30 and 60 min after water access. Samples were centrifuged
immediately (10,000 g, 1 min) and later analyzed for
Posmol measured from two 20-µl aliquots by freezing-point
depression using a microosmometer (model 3360; Advanced Instruments,
Norwood, MA).
Statistical analysis.
All data are expressed as means ± SE. Body weight, baseline MAP
and lability, and baroreflex responses were analyzed by ANOVA (Systat;
SPSS) followed by a Fisher's post hoc test. Baroreflex gain was
calculated by dividing the absolute change in HR by the change in MAP.
Water intakes, MAP, and HR were analyzed by a two-way ANOVA with
repeated measures. Latencies to drink were analyzed similarly, but only
rats that drank during the test were used in the analysis. When
significant F values were obtained for the group or dose factor, one-way ANOVA was performed at each time followed by a Fisher's or layered Bonferroni post hoc test, respectively. The repeated-measures variable was analyzed by a repeated-measures ANOVA
followed by paired t-tests with layered Bonferroni
correction to compare each time with baseline values. Urine volume,
urinary Na+ and K+ excretion, and
Posmol were analyzed similarly.
The percentages of rats that drank during each experiment were compared
between treatments and within each group by a Fisher's Exact Test.
When water intake or latency to drink was plotted as a function of
baroreflex gain, the distribution of complete SAD rats vs. partial SAD
or control rats was compared by a Fisher's Exact Test. A horizontal
line was drawn just below the lowest water intake or just above the
longest latency to drink among the complete SAD rats, and the numbers
of rats above and below the line were compared with the numbers of
partial SAD or control rats situated similarly. Rats that did not drink
were assigned latencies to drink of 60 min for purposes of comparison.
Plasma ANG II levels were log transformed and analyzed by one-way
repeated-measures ANOVA followed by appropriate post hoc testing as
described above. Plasma ANG II levels in complete SAD rats and control
rats infused with 40 and 100 ng · kg1 · min1 ANG II were
compared by a two-way ANOVA with repeated measures. Plasma ANG II
levels associated with experimental models known to induce thirst were
compared with baseline values by independent t-tests. These
plasma ANG II levels also were compared by independent t-tests with plasma ANG II levels at 15 min after each
infusion dose of ANG II.
In all statistical comparisons, a P value <0.05 was
considered to be significant.
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RESULTS |
Effect of sinoaortic denervation on drinking behavior during an
infusion of ANG II.
Baroreflex responses to PE, SNP, and PBG for complete SAD, partial SAD,
and control rats are presented in Table
1. Baseline MAP and HR were not different
between groups (Table 1; P > 0.8 from overall ANOVAs),
and MAP of complete SAD rats was significantly more labile than that of
control or partial SAD rats (Table 1), as reported previously
(20, 25). By definition, complete SAD rats displayed no
change in HR to intravenous bolus injection of PE and SNP. Furthermore,
complete SAD rats had a greater change in MAP in response to PE and SNP
than control rats did, presumably because of a loss of baroreflex
buffering. Partial SAD rats displayed HR changes in response to PE and
SNP that were significantly smaller than those in control rats but
significantly greater than those in complete SAD rats (Table 1).
Complete SAD and partial SAD rats displayed bradycardic and hypotensive
responses to the PBG that were not different from those of control rats
(Table 1).
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Table 1.
Phenylphrine, sodium nitroprusside, and phenyl biguanide evoked changes
in mean arterial blood pressure and heart rate for control and partial
or complete sinoaortic-denervated rats
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An intravenous infusion of ANG II produced significant changes in
drinking behavior in complete SAD rats (Figs.
1 and 2). As the dose of ANG II increased, complete SAD rats drank more water and
displayed shorter latencies to drink compared with the next smaller
dose (Figs. 1 and 2). With 40, 100, and 250 ng · kg1 · min1 ANG II,
complete SAD rats ingested significantly more water compared with
control or partial SAD rats during the 60-min test (Figs. 1 and
2A). Furthermore, complete SAD rats displayed significantly shorter latencies to drink compared with control or partial SAD rats
infused with 100 and 250 ng · kg1 · min1 ANG II
(Fig. 2B). Although latencies to drink were not
statistically significant between groups at 40 ng · kg1 · min1 ANG II, a
greater percentage of complete SAD rats drank during the 60-min test
compared with control or partial SAD rats given this dose (Table
2). No differences were observed in water
intakes or latency to drink between the three groups during the
infusion of 10 ng · kg1 · min1 ANG II.
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Fig. 1.
Cumulative mean ± SE water intakes for complete
sinoaortic-denervated (SAD), partial SAD, and control rats infused with
10, 40, 100, or 250 ng · kg1 · min1 ANG II (25 µl/min iv). Baroreflex responses for these rats are presented in
Table 1. Complete SAD rats drank significantly more water than partial
and control rats in response to 40, 100, and 250 ng · kg1 · min1 ANG II
(* P < 0.05) but not when infused with 10 ng · kg1 · min1 ANG II
(P > 0.75 for overall ANOVA). Partial SAD and control
rats drank similar amounts of water at every time with every infusion
dose of ANG II. Note that the scales in the y-axis are not
uniform.
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Fig. 2.
Mean ± SE 60-min water intakes (A) and
latencies to drink (B) of complete SAD, partial SAD, and
control rats infused with 10, 40, 100, and 250 ng · kg1 · min1 ANG II (25 µl/min iv) and plotted on a log scale of dose of ANG II. Complete SAD
rats drank significantly more water at each dose of ANG II compared
with the next lower dose. No differences in latency to drink were
observed between groups at 10 or 40 ng · kg1 · min1 ANG II;
however, a greater percentage of complete SAD rats drank at 40 ng · kg1 · min1 compared
with partial SAD or control rats (see Table 2). Only rats that drank
during the 60-min test were included in this analysis of latency to
drink. * Significant differences between complete SAD rats and
partial SAD or control rats (P <0.05). #Significant
difference from next lower dose of ANG II (P <0.05).
Similar statistical differences were detected when the dose effect was
analyzed by a repeated-measures ANOVA with the exclusion of 2 rats
receiving only 10 and 100 ng · kg1 · min1 (data not
shown).
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Scatter plots of 60-min water intake or latency to drink during an
infusion of 40 or 100 ng · kg1 · min1 ANG II
plotted as a function of baroreflex gain from the PE baroreflex test
are presented in Fig. 3 and show the
importance of studying complete SAD rats. By definition, all complete
SAD rats had a baroreflex gain equal to zero, and the majority of these
rats ingested more water compared with control rats at both 40 and 100 ng · kg1 · min1 ANG II
(Fig. 3). Although the baroreflex gain was significantly blunted in
every partial SAD rat compared with control rats, partial SAD rats
usually drank less water than complete SAD rats but similar amounts of
water as control rats when infused with 40 and 100 ng · kg1 · min1 ANG II
(Fig. 3). Similarly, complete SAD rats generally drank sooner than
control or partial SAD rats infused with 40 and 100 ng · kg1 · min1 ANG II
(Fig. 3).
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Fig. 3.
The 60-min water intake (top) or latency to
drink (bottom) plotted as a function of baroreflex gain for
complete SAD, partial SAD, and control rats infused with 40 or 100 ng · kg1 · min1 ANG II.
Rats that did not drink during the test were assigned latencies to
drink equal to 60 min for purposes of comparison. The baroreflex gain
was taken from the PE baroreflex test. By definition, complete SAD rats
displayed a baroreflex gain of 0 (vertical line). The majority of
complete SAD rats ingested more water and displayed shorter latencies
to drink than control or partial SAD rats when infused with 40 or 100 ng · kg1 · min1 ANG II
(P < 0.05). Although every partial SAD rat displayed a
blunted baroreflex gain compared with control rats, the majority of
partial SAD rats ingested amounts of water and displayed latencies to
drink similar to those of control rats infused with 40 and 100 ng · kg1 · min1 ANG II. HR,
heart rate; MAP, mean arterial pressure.
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The infusion of 40, 100, and 250 ng · kg1 · min1 ANG II
produced significant increases in MAP of complete SAD, partial SAD, and
control rats (Fig. 4). Each of these
infusion doses of ANG II produced greater elevations in MAP in complete
SAD rats than in control rats (P < 0.05; Fig. 4).
Compared with control rats, partial SAD rats also showed an exaggerated
pressor response to ANG II (P < 0.05); however,
complete SAD rats displayed significantly higher MAP values than
partial SAD rats infused with 40 and 100 ng · kg1 · min1 ANG II
at 3 and 15 min (P < 0.05).
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Fig. 4.
Mean ± SE MAP for complete SAD, partial SAD, and
control rats infused with 10, 40, 100, and 250 ng · kg1 · min1 ANG II (25 µl/min iv). The infusion of ANG II significantly increased MAP above
baseline values in complete SAD, partial SAD, and control rats at 40, 100, and 250 ng · kg1 · min1
(P < 0.01). Furthermore, the infusion of ANG II
resulted in a greater increase in MAP in complete SAD rats compared
with control rats at 40, 100, and 250 ng · kg1 · min1
(P < 0.05). The smallest dose of ANG II (10 ng · kg1 · min1) did not
significantly change MAP from baseline values in any group
(P > 0.6 from overall ANOVA).
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Not surprisingly, infusion of 40, 100, and 250 ng · kg1 · min1 ANG II
caused significant decreases in HR in control rats throughout the
60-min test (Fig. 5). In contrast, these
ANG II infusions significantly increased HR above baseline values in
complete SAD rats (Fig. 5), whereas the HR of partial SAD rats remained
unchanged from baseline values with each dose of ANG II. The infusion
of 10 ng · kg1 · min1 ANG
II did not alter MAP or HR in any group (Figs. 4 and 5).
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Fig. 5.
Mean ± SE HR for complete SAD, partial SAD, and
control rats infused with 10, 40, 100, and 250 ng · kg1 · min1 ANG II (25 µl/min iv). As expected, control rats displayed a significant
bradycardia when pressor doses of ANG II (40, 100, and 250 ng · kg1 · min1) were
infused (P < 0.01). In contrast, those doses of ANG II
significantly increased HR above baseline values in complete SAD rats
(P < 0.05). However, HR did not change from baseline
values in partial SAD rats with any dose of ANG II (P > 0.05 from overall ANOVAs). Thus HR of partial SAD rats were
significantly different from complete SAD and control rats during 40, 100, and 250 ng · kg1 · min1 ANG II
(P < 0.05). HR values did not change from baseline
values in any group during 10 ng · kg1 · min1 ANG II
(P > 0.6 from overall ANOVA).
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A two-way ANOVA revealed a significant effect of dose of ANG II on
urine volume and urinary Na+ and K+ excretion
and a significant effect of group on urinary volume and K+
excretion (Table 3). However, consistent
differences in urinary output were not observed between groups, thereby
suggesting that large differences in urinary excretion cannot account
for the observed differences in drinking behavior.
Effect of intravenous infusion of ANG II on plasma ANG II levels.
Each dose of ANG II tested in control rats (10, 40, 100, and 250 ng · kg1 · min1) produced a
significant and sustained increase in plasma ANG II levels above
baseline values (Fig. 6A). As
the dose increased, plasma ANG II levels were significantly greater
than those during the next lower dose of ANG II at every time point.
Similarly, infusion of 40 and 100 ng · kg1 · min1 ANG II in
complete SAD rats significantly increased plasma ANG II levels above
baseline values throughout the infusion period (Fig. 6A),
and these levels did not differ from the elevated levels in control
rats at any time (P > 0.4).
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Fig. 6.
Mean ± SE plasma ANG II levels in control (filled
symbols) and complete SAD (open symbols) rats during an intravenous
infusion of 10, 40, 100, or 250 ng · kg1 · min1 ANG II (25 µl/min iv; A) or various treatments known to evoke thirst
in rats (B). Each infusion dose of ANG II tested
significantly increased plasma ANG II levels above baseline values at
3, 15, and 45 min in control rats (P < 0.025) and
above those from the next lower dose (P < 0.05).
Furthermore, plasma ANG II levels during 40 and 100 ng · kg1 · min1 ANG II were
not significantly different between control and complete SAD rats
(P > 0.4 from overall ANOVA). Water deprivation (Dep)
for 24 h significantly raised plasma ANG II levels above baseline
values (P <0.05), and plasma ANG II levels were
significantly higher after 48 h of water deprivation. Diazoxide
(DZX) treatment (25 mg/kg iv) significantly raised plasma ANG II levels
at 30 min (P < 0.01). In contrast, an infusion of 1 M
NaCl significantly decreased plasma ANG II levels at 60 min compared
with baseline values (P < 0.05). Note that plasma ANG
II levels after 24 h of water deprivation were not different from
those during 10 ng · kg1 · min1 ANG II
(P > 0.3), whereas plasma ANG II levels after
48 h of water deprivation were not different from those during 40 ng · kg1 · min1 ANG II
(P > 0.4).
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To compare plasma ANG II levels during these infusions of ANG II with
the effects of other treatments known to evoke thirst and alter the
activity of the renin-angiotensin system, additional experiments were
performed to analyze plasma ANG II levels after 24 and 48 h of
water deprivation, DZX-induced hypotension, or intravenous infusion of
HS. Plasma ANG II levels increased significantly from baseline values
after 24 and 48 h of water deprivation (Fig. 6B), and
the effect of 48 h of water deprivation was greater than that of
24 h of water deprivation (Fig. 6B). As expected
(22), DZX-induced hypotension was accompanied by an even
greater increase in plasma ANG II levels (Fig. 6B). In
contrast, an infusion of 1 M NaCl significantly reduced plasma ANG II
levels (Fig. 6B).
When the plasma ANG II levels after these treatments were compared with
15-min values during the infusions of ANG II, 24 h of water
deprivation were not significantly different from 10 ng · kg1 · min1 ANG II
(P > 0.4), and 48 h of water deprivation were not
significantly different from 40 ng · kg1 · min1 ANG II
(P > 0.3). However, plasma ANG II levels after 24 and 48 h of water deprivation were significantly lower than the levels observed during the two higher doses of ANG II tested. Indeed, plasma
ANG II levels during 100 and 250 ng · kg1 · min1 ANG II were
much greater than plasma ANG II levels after any of the treatments
examined (Fig. 6).
Effects of sinoaortic denervation on the AP-evoked inhibition of
drinking behavior during increases in Posmol.
Baroreflex responses for control, partial SAD, and complete SAD rats
used in the hyperosmolality experiments are presented in Table 1 and
are similar to those discussed above for ANG II experiments. Again,
baseline MAP and HR were not different between groups (Table 1;
P > 0.2 from overall ANOVAs), and MAP of complete SAD
rats was significantly more labile than that of control or partial SAD
rats (Table 1).
Control rats treated with HS + SLN drank significant amounts of water
and displayed a short latency to drink (3.0 ± 0.4 min). In
agreement with previous findings (21), an infusion of PE significantly increased MAP above baseline values and inhibited drinking behavior. Control rats treated with HS + PE ingested significantly less water than control rats treated with HS + SLN (Fig.
7) and displayed a significantly longer
latency to drink than those treated with HS + SLN (7.8 ± 1.7 vs.
3.0 ± 0.4 min, respectively; P < 0.05).
Furthermore, a significantly smaller percentage of control rats treated
with HS + PE drank during the test compared with control rats treated
with HS + SLN (Table 4).
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Fig. 7.
Mean ± SE cumulative water intake, MAP, and HR of
complete SAD, partial SAD, and control rats infused with 1 M NaCl (HS,
2 ml/h for 2 h iv) and then either phenylephrine (PE, 4 µg · kg1 · min1) or
isotonic saline (SLN, 25 µl/min). As expected (21), the
infusion of PE significantly reduced water intake while increasing MAP
in control rats (P < 0.01). In contrast, the infusion
of PE did not significantly reduce water intake (P > 0.5) in complete SAD rats despite producing even larger elevations in
MAP (P < 0.05). In fact, water intakes of complete SAD
rats treated with HS + PE and HS + SLN did not
significantly differ from each other or from control rats treated with
HS + SLN (P > 0.5). An infusion of PE in partial
SAD rats significantly reduced water intake and raised MAP as in
control rats treated with HS + PE (P < 0.05). As
expected, an infusion of PE produced a significant bradycardia in
control rats at each time (P < 0.05) but not in
complete or partial SAD rats.
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Table 4.
Latencies to drink and percentage of control, partial SAD, or complete
SAD rats that drank in response to an iv infusion of 1 M NaCl plus an
infusion of either PE (4 µg · kg1 · min1) or
SLN (25 µl/min)
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To determine whether arterial baroreceptor afferents mediate the
inhibitory effect of an acute increase in AP on thirst stimulated by
hyperosmolality, SAD rats were treated with HS + PE or HS + SLN. If
arterial baroreceptor afferents mediate this inhibitory effect, then
complete SAD rats treated with HS + PE should display drinking
responses similar to complete SAD or control rats treated with HS + SLN. In fact, all complete SAD rats treated with HS + PE drank (Table
4), displayed a short latency to drink (Table 4), and ingested amounts
of water that were not different from complete SAD or control rats
treated with HS + SLN despite a significantly elevated MAP throughout
the test period (Fig. 7). In contrast, partial SAD rats treated with HS + PE ingested significantly less water than partial SAD or control rats
treated with HS + SLN (Fig. 7).
Because of the loss of baroreceptor afferent fibers, complete SAD rats
treated with HS + PE displayed no significant change in HR despite
marked elevations in MAP (Fig. 7). As reported previously (21), control rats treated with HS + PE displayed a
significant bradycardia compared with baseline values, whereas partial
SAD rats treated with HS + PE displayed no significant changes in HR at
any time (Fig. 7).
The inhibition of drinking behavior resulting from the PE infusion
occurred in control and partial SAD rats despite significant elevations
in Posmol (Table 5). The
infusion of HS significantly raised Posmol in both
treatment groups; however, Posmol of control and partial
SAD rats treated with HS + PE remained elevated at 30 min despite
access to water (Table 5). In contrast, Posmol of complete
SAD rats treated with HS + PE returned to baseline levels at 30 min and
did not differ from Posmol of control or complete SAD rats
treated with HS + SLN (Table 5).
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Table 5.
Plasma osmolality for control and SAD rats infused with 1 M NaCl (2ml/h
iv) followed by either SLN (25 µl/min) or PE (4 µg · kg1 · min1).
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Urine volumes and excretion of Na+ or K+ were
not statistically different between control, partial SAD, and complete
SAD rats before or during water access regardless of treatment
condition (data not shown). Furthermore, these values are not
statistically different from those reported previously in control rats
treated identically (21).
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DISCUSSION |
An acute increase in AP has been demonstrated to inhibit thirst
stimulated by ANG II, hyperosmolality, or hypovolemia in rats (3,
4, 13, 17, 21). However, the afferent signal(s) mediating this
inhibitory effect has not been established. The primary finding of the
present study is that sinoaortic denervation eliminates the inhibition
of thirst resulting from an acute increase in AP. Complete SAD rats
drank sooner and ingested more water compared with control rats (or
partial SAD rats) during an intravenous infusion of ANG II. Similarly,
PE-induced increases in AP failed to inhibit drinking behavior in
complete SAD rats that were infused intravenously with HS. Thus it
appears that arterial baroreceptors play a critical role in mediating
the inhibition of thirst during an acute increase in AP.
Complete SAD enhances drinking behavior during an infusion of ANG
II.
The primary way by which the central nervous system detects changes in
AP is through an afferent neural signal arising from arterial
baroreceptors. Because removal of these afferent nerves eliminates the
reflexive changes in sympathetic nerve activity and HR to changes in AP
(1, 2, 27), we hypothesized that complete removal of these
afferents would eliminate the pressure-dependent inhibition of thirst
during an intravenous infusion of ANG II. Although previous reports
suggest that sinoaortic denervation does not alter water intakes
stimulated by peripherally administered ANG II (10, 16),
the SAD rats in those studies may not have been completely denervated,
as discussed below. On the other hand, complete removal of both
arterial and cardiopulmonary afferents, by surgical denervation in dogs
(11) or electrolytic lesion of NTS in rats
(18), resulted in greater water intakes and shortened latencies to drink during intravenous infusions of pressor doses of ANG
II. Therefore, arterial and/or cardiopulmonary stretch receptors
mediate the AP-evoked inhibition of drinking behavior during an
infusion of ANG II, but it was unclear whether one or both types of
afferents mediate this inhibition.
In the present study, complete sinoaortic denervation resulted in
significantly shorter latencies to drink and greater water intakes
during an infusion of pressor doses of ANG II, thereby suggesting that
arterial baroreceptors play a critical role in mediating the inhibition
of thirst during an acute increase in AP. If arterial baroreceptors
predominantly mediate this inhibition, then the latencies to drink and
water intakes of complete SAD rats should be similar to those observed
in rats when the ANG II-induced increase in AP was attenuated with a
vasodilator (4, 17, 21). Indeed, a comparison of the
present data with our recently published findings, using the same
general procedures as in the present study (21), confirms
this hypothesis. Complete SAD rats infused with 100 ng · kg1 · min1 ANG II and
control rats (n = 8) infused with 100 ng · kg1 · min1 ANG II plus
intravenous administration of DZX (10 mg/kg iv) display similar
latencies to drink (9.3 ± 1.1 vs. 8.0 ± 1.2 min,
respectively; P > 0.4) and ingest similar amounts of
water during a 60-min test (8.3 ± 1.0 vs. 8.2 ± 0.7 ml,
respectively, P > 0.9). Therefore, the surgical
elimination of the neural afferent signal associated with an acute
increase in AP by complete sinoaortic denervation has the same effect
on drinking behavior stimulated by an intravenous infusion of ANG II as
the pharmacological elimination of the acute increase in AP in intact
rats. These observations suggest that the AP-evoked inhibition of
drinking behavior is mediated by arterial baroreceptor afferents.
Although a large increase in AP can elevate cardiac pressure and
stimulate mechanosensitive cardiac afferents (6), the shortened latencies and greater water intakes in our complete SAD rats
cannot be attributed to the destruction of cardiopulmonary afferents.
First, complete SAD rats exhibited normal hypotensive and bradycardic
responses to PBG, a response that is dependent on intact
cardiopulmonary afferents (26). Second, the water intakes
of complete SAD rats are similar to those of NTS-lesioned rats studied
previously in a similar protocol in this laboratory (8.3 ± 1.0 vs. 10.3 ± 0.7 ml, respectively; P > 0.1; see
Ref. 18), despite the fact that NTS lesions eliminate
neural input from cardiopulmonary and other visceral afferents. Thus it
appears that arterial baroreceptors solely mediate the inhibition of
thirst resulting from an increase in AP during an infusion of ANG II.
Drinking behavior in partial SAD rats during an infusion of ANG II.
One of the most striking observations regarding the effect of
sinoaortic denervation on ANG II-evoked thirst was the requirement that
the denervation be complete. In the present study, a denervation was
considered to be complete only when there were no reflexive changes in
HR during intravenous bolus injections of PE and SNP. Those SAD rats
exhibiting residual HR responses during baroreflex testing were
classified as partial SAD rats; these rats displayed changes in HR of
10-30 beats/min compared with 50-95 beats/min in control rats
in response to PE and SNP. With each dose of ANG II tested, partial SAD
rats displayed latencies to drink and ingested amounts of water similar
to those of weight-matched control rats (see Fig. 3). Even partial SAD
rats displaying a baroreflex gain of <0.5
beats · min1 · mmHg1 drank
water in amounts similar to control rats during infusions of 40 or 100 ng · kg1 · min1 ANG II (see
Fig. 3). The critical importance of a complete sinoaortic denervation
in studies assessing the role of arterial baroreceptor afferents has
been emphasized previously (20), and the present results
reinforce this point.
In contrast to the present study, previous reports (10,
16) have concluded that surgical removal of arterial
baroreceptor afferents in rats does not enhance ANG II-evoked thirst.
We have already highlighted the extent of baroreceptor denervation as a
critical issue in this study, and the same concern is relevant to these
previous studies (10, 16); it not clear whether the animals in those studies were completely denervated. First, neither study (10, 16) examined reflexive changes in HR in
response to decreases in AP, and the importance of assessing baroreflex function by both increases and decreases in AP has been emphasized previously (20). Furthermore, Kadekaro and colleagues
(10) assessed the completeness of the sinoaortic
denervation by measuring the changes in HR during an infusion of 2.5 µg/min ANG II. Although a lack of change in HR was interpreted as
evidence of baroreceptor denervation (10), this result may
indicate a partial denervation, since it is in distinct contrast to the
tachycardic response observed in complete SAD rats in the present study
(see Fig. 5). In another report suggesting that sinoaortic denervation
does not enhance ANG II-evoked thirst, Rettig and Johnson
(16) observed small residual changes in HR in response to
increases in AP in SAD rats. More importantly, the baroreflex testing
was performed while rats were anesthetized with ether, and a variety of
anesthetics have been shown to blunt baroreflex changes in HR
(20, 23). Therefore, it seems likely that the SAD rats of
Rettig and Johnson (16) would have displayed greater
changes in HR had baroreflex testing been performed in unanesthetized
rats, like the partial SAD rats in the present study. Thus it now
appears likely that the previously reported failure of sinoaortic
denervation to enhance thirst in rats stimulated by peripherally
administered ANG II results from an incomplete deafferentation of
arterial baroreceptors.
It is noteworthy that the drinking behavior of partial SAD rats in
response to pressor doses of ANG II did not fall between that of
control and complete SAD rats, despite the partial loss of baroreceptor
afferents. In explanation, partial SAD rats exhibited greater
elevations in MAP than control rats during ANG II infusions, and this
greater elevation in MAP may have provided a greater inhibitory signal
to drinking behavior in partial SAD rats than in control rats since
partial SAD rats still are capable of detecting changes in AP. It would
be interesting to determine whether water intakes and latencies to
drink of partial SAD rats would fall between those of control and
complete SAD rats if MAP was clamped at a similar level in all three
groups. On the other hand, previous reports suggest that partial SAD
rats appear similar to control rats in regard to certain other
responses (19, 20), and this may extend to AP-evoked
inhibition of drinking behavior during an intravenous infusion of ANG II.
Cardiovascular responses to ANG II in SAD rats.
An intravenous infusion of 40, 100, and 250 ng · kg1 · min1 ANG II
produced significant increases in MAP and decreases in HR in control
rats. In contrast, complete SAD rats displayed greater elevations in
MAP and a significant tachycardia throughout the test. Similar
increases in HR during an infusion of ANG II have been reported in
baroreceptor-denervated dogs (5, 7) and rats
(18). This response likely results from direct
chronotropic effects of ANG II via AT1 receptors
(14) and an increase in sympathetic outflow (5, 14,
27). On the other hand, the HR of partial SAD rats infused with
ANG II did not change from baseline values, which probably results from
a small residual baroreflex-induced bradycardia being cancelled by the
tachycardic effects of ANG II. The larger increase in AP observed
during the ANG II infusion in partial and complete SAD rats compared
with control rats most likely results from the blunting or loss of baroreceptor-mediated sympathoinhibition and an increase in cardiac output.
Physiological significance of plasma ANG II levels.
The enhancement of thirst stimulated by the infusion of ANG II in
complete SAD rats cannot be explained by differences in plasma ANG II
levels because complete SAD and control rats exhibited similar
sustained increases in plasma ANG II levels during infusion of 40 or
100 ng · kg1 · min1 ANG II.
In agreement with previous studies (9, 15), the increases
in plasma ANG II levels produced by the larger infusion doses of ANG II
do not resemble the plasma ANG II levels produced by any treatment
examined in the present study; however, the increase in plasma ANG II
levels observed during infusion of 40 ng · kg1 · min1 ANG II was
similar to that observed after 48 h of water deprivation (see Fig.
6). Because the enhancement of drinking behavior during an infusion of
ANG II was observed in complete SAD rats at this dose, the present
results suggest that arterial baroreceptors are capable of influencing
drinking behavior in association with physiological increases in plasma
ANG II levels.
Sinoaortic denervation eliminates AP-evoked inhibition of drinking
behavior during increases in Posmol.
Previously, we reported that increases in AP lengthen the latency to
drink and reduce water intake stimulated by increases in
Posmol and that this inhibitory effect is related to the
evoked increase in AP in the range of ~100 to ~160 mmHg
(21). The present study confirms those findings but also
demonstrates that complete SAD rats treated with HS + PE behave
similarly to control rats treated with HS + SLN despite significant
differences in MAP in the two groups. These effects cannot be
attributed to differences in Posmol, urinary excretion of
the Na+ load, or differences in MAP between complete SAD
and control rats. Furthermore, complete SAD rats treated with HS + SLN
displayed similar latencies to drink and ingested comparable amounts of water as control rats treated with HS + SLN, thereby suggesting that
complete SAD rats are not more sensitive to the hyperosmotic signal for
thirst. Again, the degree of the denervation was critical for the
elimination of this inhibitory effect; partial SAD rats treated with HS + PE displayed latencies to drink and water intakes that were not
different from control rats treated with HS + PE (see Fig. 7). Thus
arterial baroreceptors mediate AP-evoked inhibition of thirst
regardless of whether drinking behavior is stimulated by
hyperosmolality or by peripherally administered ANG II.
Drinking behavior and the baroreceptor reflex.
When water intake is plotted as a function of MAP, the relationship
resembles the well-known baroreceptor reflex curve relating changes in
HR or sympathetic nerve activity to changes in MAP (21).
As MAP increased, water intake decreased whether it was stimulated by
ANG II, hyperosmolality, or hypovolemia in rats. Furthermore, this
inhibitory effect was directly related to the increase in AP in the
range of ~100 to ~160 mmHg and appeared to be equivalent across
these three thirst stimuli (21). Because complete removal
of arterial baroreceptor afferents is known to eliminate the reflexive
changes in HR or sympathetic nerve activity during acute increases in
AP (1, 2, 27), it seemed plausible that complete removal
of these same afferents would eliminate the inhibitory effect of an
acute increase in AP on drinking behavior. As expected, when water
intakes of complete SAD rats infused with 100 ng · kg1 · min1 ANG II are
expressed as a percentage of the water intakes of control rats infused
with 100 ng · kg1 · min1
ANG II plus DZX (10 mg/kg iv), water intakes of complete SAD rats were
equivalent to those of control rats infused with 100 ng · kg1 · min1 ANG II plus
DZX (10 or 20 mg/kg iv) despite significant differences in MAP (Fig.
8A). Similarly, water intakes
of complete SAD rats treated with HS + PE were equivalent to control or
complete SAD rats treated with HS + SLN (Fig. 8B) despite
significant differences in MAP. With both ANG II and hyperosmolality,
the water intakes of partial SAD rats with an elevated AP were
equivalent to control rats with a similar increase in MAP. Therefore,
complete removal of arterial baroreceptor afferents eliminates the
AP-evoked inhibitory influence on drinking behavior when stimulated by
ANG II or hyperosmolality.
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Fig. 8.
Mean ± SE water intakes expressed as a percentage
of control values plotted as a function of MAP for complete SAD,
partial SAD, and control rats. Drinking behavior was stimulated either
by ANG II (A) or hyperosmolality (B). Water
intakes were 15-min values expressed as a percentage of the mean value
for rats treated with 100 ng · kg1 · min1 ANG II plus
DZX (10 mg/kg iv; A), as previously reported from our
laboratory (21), and for control rats treated with
HS + SLN (B). MAP was clamped at different levels by
varying the dose of DZX (0, 5, 10, and 20 mg/kg iv) for ANG II
experiments or the dose of PE (2, 4, and 8 µg · kg1 · min1 iv).
Despite significantly elevated MAP, water intakes of complete SAD rats
fell near or on the dotted line representing 100% of control water
intake. In fact, a significant correlation was found when the
percentage of control water intakes was plotted as a function of MAP to
the baroreflex algorithm for control rats (r = 0.67 for
ANG II, r = 0.66 for hyperosmolality). However, the
majority of complete SAD rats fell outside the 95% confidence interval
in both ANG II and hyperosmolality experiments when rats were
hypertensive, whereas the majority of partial SAD rats fell within the
95% confidence interval.
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Perspectives
The baroreflex plays an important role in maintaining proper
perfusion of tissues when animals are faced with perturbations in AP.
Changes in AP are sensed by stretch receptors, relayed through a neural
afferent signal to the central nervous system, and evoke changes in the
activity of sympathetic and parasympathetic nervous systems as well as
hypothalamic endocrine systems (24). During an increase in
AP, these reflex responses include decreases in cardiac output,
vascular resistance, and firing rate of putative vasopressin neurons.
In addition, an increase in AP leads to an increase in the renal
excretion of water and Na+ thereby decreasing intravascular
volume and restoring AP. All of these responses act in concert to
restore AP toward original levels. In an analogous manner,
perturbations in AP might be expected to limit the ingestion of water
and Na+, thereby aiding in the restoration of AP. Indeed,
we have previously demonstrated that acute increases in AP inhibit
drinking behavior stimulated by ANG II, hyperosmolality, and
hypovolemia in rats (21). Similar to the effects of
complete removal of arterial baroreceptor afferents on reflexive
changes in sympathetic nerve activity and HR during acute changes in AP
(1, 2, 27), the present study demonstrates that complete
sinoaortic denervation eliminated the inhibitory effect of acute
increases in AP on drinking behavior. Therefore, influences of
baroreceptors on cardiovascular homeostasis should include behavioral
responses in addition to neural, endocrine, and renal responses.
| |
ACKNOWLEDGEMENTS |
We thank Ruwani Bandaranayake and Jason Devlin for technical
assistance and Dr. Ian Reid for the generous gift of the ANG II antibody.
| |
FOOTNOTES |
This research was supported by National Institutes of Health Grants
MH-25140 (E. M. Stricker) and HL-55687 (A. F. Sved). S. D. Stocker was supported by an Andrew Mellon Predoctoral Fellowship.
Present address for S. D. Stocker: Dept. of Physiology, Univ. of Texas
Health Sciences Center-San Antonio, 7703 Floyd Curl Dr., San Antonio,
TX 78229.
Address for reprint requests and other correspondence:
A. F. Sved, Dept. of Neuroscience, Univ. of Pittsburgh, 446 Crawford Hall, Pittsburgh, PA 15260 (E-mail:
sved{at}bns.pitt.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.
10.1152/ajpregu.00651.2001
Received 2 November 2001; accepted in final form 18 January 2002.
| |
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TOP
ABSTRACT
INTRODUCTION
