Vol. 279, Issue 1, H58-H66, July 2000
SHR Y chromosome enhances the nocturnal blood pressure in
socially interacting rats
Ann
Caplea,
Darcie
Seachrist,
Gail
Dunphy, and
Daniel
Ely
Department of Biology, The University of Akron, Akron, Ohio
44325-3908
 |
ABSTRACT |
Our objective was to test the
hypothesis that nocturnal mean arterial pressure (MAP), heart rate
(HR), and activity would be increased in 1) colony over
individually caged rats and 2) the spontaneously
hypertensive rat (SHR) Y chromosome strain (SHR/y colony) compared with
Wistar-Kyoto (WKY) rats. MAP, HR, and activity were monitored using
radiotelemetry. The nocturnal MAP rise expressed as the percentage
change in MAP from light to dark was increased (P < 0.05) in the SHR/y colony. The SHR Y chromosome increased MAP in both
the colony and caged groups compared with WKY (P < 0.001). The SHR/y colony animals spent 23% of a 24-h period at a MAP
>120 mmHg, whereas the WKY colony animals spent 2% of a 24-h period
in this range. The MAP of the SHR/y colony on clonidine was reduced
(P < 0.001) to WKY baseline values. Activity but not HR was increased (P < 0.01) in the WKY and SHR/y
colonies compared with caged animals. In conclusion, colony housing and
the SHR Y chromosome increased MAP compared with individually caged housing.
colony; clonidine; sympathetic nervous system
| |
INTRODUCTION |
THE BENEFIT OF 24-h
ambulatory monitoring of blood pressure (BP) has been shown
(39, 48). Also, the importance of considering behavioral factors on the daily variation of BP has been emphasized (20). In the course of 24 h, humans interact in a
complex social environment. Because of this, it is important to monitor
BP and heart rate (HR) during various types of social interaction.
Circadian variations in BP and HR are thought to be related to ongoing
behavioral changes partially associated with elevated levels of
sympathetic activity during the active cycle (14, 47). This may contribute to the evidence from human and
experimental animal studies showing that differences between light and
dark cycle BP and HR are usually greater in hypertensive compared with normotensive individuals (14, 47). Otsuka et
al. (33) showed that excessive BP amplitude over 48 h
increased the relative risk for ischemic stroke and nephropathy in humans.
Previous circadian rhythm studies of the spontaneously hypertensive rat
(SHR) and the normotensive Wistar-Kyoto (WKY) rat have shown that BP,
HR, and activity are elevated during the dark cycle compared with the
light cycle (14, 47). In these studies, all
experimental animals were individually housed. Evidence from several
laboratories suggests that there are physiological differences in
colony-housed animals compared with those individually housed (11, 12, 17). For instance,
housing animals under different environmental conditions has influenced
behavioral, hormonal, immunological, and biochemical parameters
indicative of a stress response (3, 4,
26, 34).
Behavioral studies have shown that the SHR is hyperreactive to
environmental stimuli (43) and has exaggerated responses to classical fear conditioning (23, 25,
29). Also, WKY differ significantly in behavior
(1) compared with other normotensive strains. A review of
the WKY and SHR behavioral differences (44) shows a
complex array of different behaviors. For instance, Hendley et al.
(16) have developed a strain of WKY with hyperactivity but
without hypertension to show a separation of the two phenotypes, which
confirms that different behavioral characteristics are associated with
hypertension, not just hyperactivity.
Therefore, there is a need to study cardiovascular regulation during
daily life events to dissect the complex physiological processes
involved (27). Our laboratory has been studying
cardiovascular parameters in social groupings and the role of social
rank on BP and neuroendocrine profiles for several years
(8, 10). BP measurement by radiotelemetry
permits the continuous monitoring of cardiovascular parameters in
freely moving, untethered animals. Such measurements can be analyzed
for circadian BP, HR, and activity (41).
Colony housing provides a unique environment quite different from
traditional group housing (11, 17,
18). Male and female rats interact, developing hierarchal
and often aggressive behavior between the male rats. Therefore, we
hypothesized that animals housed in a colony would have higher BP
during the active dark cycle due to increased social interaction
compared with animals housed individually in cages. Our first objective
was to determine if the circadian rhythms of mean arterial pressure
(MAP), HR, and activity were greater in male rats socially interacting
in a colony with competition for food, females, and territory compared with that of males individually caged. Second, our laboratory has shown
that the Y chromosome from a SHR father when backcrossed for 17 generations into a normotensive WKY rat increased sympathetic nervous
system (SNS) indexes (7) and maintained an increase in BP
of ~15-20 mmHg, even after 11 generations (9).
Therefore, our second objective was to determine if the WKY male with
an SHR Y chromosome (SHR/y consomic) and increased SNS activity will have increased nocturnal BP, HR, and activity due to enhanced SNS
activity. We proposed that clonidine blockade of the SNS would reduce
the nocturnal BP, HR, and activity to values similar to the
normotensive WKY.
| |
METHODS |
Rat Strains
The parental WKY/hsd and SHR/hsd strains were originally
obtained from Harlan Sprague Dawley (Indianapolis, IN) and have been inbred in our laboratory since 1981. In the following studies, we also
used the consomic strain (SHR/y ua) developed in our laboratory that
has the SHR Y chromosome backcrossed to the WKY background for 17 generations (45). Briefly, a WKY female was mated with an
SHR male. The males of the F1 generation were mated with a WKY female.
This protocol was continued for 17 generations. As a result, 99.9% of
the autosomes of the SHR/y strain are from the WKY strain, and only the
Y chromosome is from the SHR strain. Therefore, we compared the WKY and
SHR/y in this experiment, and differences in BP, HR, or activity would
implicate the Y chromosome because this is the only chromosome that is
different between the two strains.
Rats were acclimated from birth to a 12:12-h light
(0600-1800)-dark (1800-0600) cycle,
and this was continued throughout the entire experimental procedure
with constant temperature (27-29°C) and humidity (50-70%).
Before introduction into experimental groups, all rats were maintained
on rat chow (Agway 3000; TR Last, Gibsonia, PA) and tap water ad
libitum. Clonidine was administered in the food at a dosage of 120 µg/20 g food (7). All animals were treated in a humane
manner according to National Institutes of Health guidelines, and all
experiments were approved by the University of Akron Institutional
Animal Use and Care Committee.
Telemetry Equipment and Data Acquisition
MAP, HR, and activity were measured using a telemetry system and
the Dataquest IV data acquisition system (Data Sciences, Roseville,
MN). Animals were anesthetized with Brevital sodium (50 mg/kg ip; Eli
Lilly, Indianapolis, IN), and the transmitters were surgically
implanted. Briefly, a midline abdominal incision was made, and the
descending aorta was exposed between the renal vessels and the
bifurcation of the femorals. The vena cava and aorta were separated,
and a ligature was placed under the aorta to restrict blood flow
caudally. A 21-gauge needle was used to make a small hole in the aorta
and guide the flexible catheter tip of the radio transmitter into the
aorta. The catheter was secured in place with a bonded patch (Vetbond;
3M Animal Care Products, St. Paul, MN). The transmitter was placed in
the peritoneal cavity and sutured to the abdominal wall as the midline
incision was closed. Penicillin was administered (2,500 units im)
immediately after the surgery. Animals were placed in individual
recovery cages for 1 wk.
A measurement of cardiovascular and activity parameters was recorded
and saved every 30 min. Data were retrieved using the sort Utility
software from the Dataquest program. To illustrate the circadian
pattern, sampling occurred one time in a 30-min period (sampling
time = 3 s). The data were then averaged to obtain a single
value every hour for each of the 24 h in 1 day. The data represent
a single day for each rat. Because of the design of the colony, only
one transmitter could be "on" for a given day, even though many
implanted rats were housed in the colony. Each day, the previously
recorded rat was "turned off," and a new rat was "turned on."
After all of the rats were assessed, clonidine was added to the food,
and a new round of data collection was established. The individually
caged animals were similarly recorded and analyzed for a single day.
The three-way ANOVA work sheet included 24 data points of BP and HR for
each rat indexed by strain, housing, and time (Table
1). Dark cycle BP and HR were calculated as the average of the readings between 6:00 PM and 5:00 AM, and the
light cycle BP and HR were calculated as the average of the remaining
readings for each rat. The three-way ANOVA work sheet included one dark
and one light BP for each rat indexed by strain, housing, and cycle
(Table 2). Activity counts were obtained
by the system by monitoring changes in the signal strength that
occurred as a result of movement of the transmitter. These data were
used for statistics and to generate graphs.
Experimental Groups
Individually caged.
Adult male (300-350 g) WKY (n = 6) and SHR/y
(n = 6) rats were randomly selected from stock cages.
Each rat was implanted with a transmitter as previously described,
housed individually in clear plastic cages (33 × 24 × 15 cm), and allowed to recover 1 wk before data were recorded and
analyzed. A receiver was placed under each individual cage. The
individual cages were placed on a four-tier rack, 3-4 cages/tier
in a separate room isolated from any other animals.
Colony-population cage.
One colony was set up for the WKY strain and one for the SHR/y strain.
The eight adult male rats were implanted as previously described and
allowed to recover at least 1 wk before being placed in the colony. In
addition, eight strain-matched adult female rats were randomly selected
and placed in the colony without instrumentation. The colony consisted
of a large center box (1.23 m × 1.23 m × 15 cm) and four
smaller (33 × 24 × 15 cm) side boxes that contained food
and water (8). Rats were free to move anywhere within the
colony. Eight receivers were strategically placed under the center area
and side nest boxes to ensure that cardiovascular and activity
parameters could be monitored at all times (Fig. 1). Because of frequency overlap, only
one rat could be monitored at a given time; all other radio
transmitters were turned off as previously described. The data
collected by all receivers were then used for the hourly average for
that rat.
Statistics
Data are expressed as means ± SE. Differences between
groups or time periods were analyzed by two- or three-way ANOVA. Tukey tests were used after ANOVA for pairwise comparisons. Significance was
assumed at P < 0.05.
| |
RESULTS |
The SHR Y chromosome significantly increased MAP in individually
caged rats (Fig. 2A; 2-way
ANOVA, P < 0.0001) and with colony housing (Fig.
2B; 2-way ANOVA, P < 0.0001). There was a
significant difference comparing strain, housing, and time (Table 1;
3-way ANOVA: strain P < 0.001; housing
P = 0.039; time P = 0.001).
View larger version (32K):
[in this window]
[in a new window]
|
Fig. 2.
Twenty-four-hour mean arterial pressure (MAP) in
Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR)/Y chromosome
(y) rats in caged (A) and colony (B) housing. MAP
expressed as means ± SE. There was a significant difference
comparing strain, housing, and time [3-way ANOVA: strain degrees of
freedom (df) = 1, F = 106.823, P < 0.001; housing df = 1, F = 4.265, P = 0.039; time df = 23, F = 3.944, P < 0.001]. A pairwise comparison of cage vs.
colony showed a significant difference between housing (WKY
P < 0.001; SHR/y P < 0.001). A
pairwise comparison of SHR/y vs. WKY showed that the SHR Y chromosome
significantly increased MAP in individually caged rats and with colony
housing (*** P < 0.001).
|
|
Figure 3 shows a 12-h average BP
comparing light and dark cycles in which there was a significant
difference comparing strain, housing, and cycle [Table 2; 3-way ANOVA:
strain degrees of freedom (df) = 1, F = 22.324, P < 0.001; housing df = 1, F = 0.432, P = 0.515; cycle df = 1, F = 11.432, P < 0.002]. A significant nocturnal rise in
MAP (t-test, P < 0.05) was demonstrated
in all groups except the individually caged SHR/y.
View larger version (38K):
[in this window]
[in a new window]
|
Fig. 3.
Bar graph of 12-h average MAP comparing light and dark
cycles of WKY and SHR/y rats in caged and colony housing. MAP expressed
as means ± SE. There was a significant difference comparing
strain, housing, and cycle (3-way ANOVA: strain df = 1, F = 22.324, P < 0.001; housing df = 1, F = 0.432, P = 0.515; cycle df = 1, F = 11.432, P < 0.002). A
significant nocturnal rise in MAP (t-test,
* P < 0.05) was demonstrated in all groups except
the individually caged SHR/y.
|
|
Although there was a significant nocturnal rise in MAP in both the WKY
and the SHR/y strains, Fig. 4
demonstrates the percentage change from light to dark to highlight the
magnitude differences between strains and treatments. The percentage of
change was determined for each rat by calculating the difference from
light to dark, as described by Uzu et al. (46). There was
no significant difference among the strains or among the housing.
However, there was a significant interaction between strain and housing
(2-way ANOVA, df = 1, F = 6.224, P = 0.0210). The nocturnal BP rise, expressed as the percentage of change
in MAP from light to dark, was significantly increased only in the
SHR/y colony (P < 0.05) compared with the SHR/y caged
group.
View larger version (24K):
[in this window]
[in a new window]
|
Fig. 4.
Bar graph of nocturnal rise in MAP in WKY and SHR/y rats
in both colony and caged housing. MAP expressed as means ± SE.
The nocturnal MAP rise is expressed as the %change in MAP from light
to dark. There was no significant difference among the strains or among
the housing. However, there was a significant interaction between
strain and housing (2-way ANOVA df = 1, F = 6.224, P = 0.0210). The nocturnal blood pressure (BP) rise,
expressed as the %change in MAP from light to dark, was significantly
increased only in the SHR/y colony (* P < 0.05)
compared with the SHR/y caged group.
|
|
An examination of the percentage of a 24-h period spent within a given
MAP range clearly indicated a shift to higher mean pressures in the
SHR/y colony vs. individual housing (Figs.
5 and 6).
Each pie graph represents 100% of time spent at the following ranges
of MAP: <100 mmHg; 100-110 mmHg; 111-120 mmHg; and >120 mmHg. These percentages were determined by counting the number of hours
each rat spent in a given MAP range. These hours (i.e., 12 h in a
range of MAP <100 mmHg) were then divided by the total number of hours
in a day (i.e., 24 h) to arrive at a percentage (i.e., 50%). Both
the colony and caged WKY animals spent 98% of a 24-h period at MAP
<120 mmHg (Fig. 5). Similar comparisons (Fig. 6) showed that the
individually caged SHR/y strain spent 16% of a 24-h period at >120
mmHg, but nearly 23% were at >120 mmHg when housed in a colony. There
was a significant strain difference (2-way ANOVA, P = 0.00077); however, there was not a significant difference among the
different housing treatments. The strain effect does not depend on the
particular type of housing, and there was not a statistically
significant interaction between strain and housing.
View larger version (29K):
[in this window]
[in a new window]
|
Fig. 5.
Pie graphs of 24-h MAP and 12:12-h light-dark averages in
WKY caged and colony rats. Each circle represents 100% of time spent
at the ranges of MAP (<100, 100-110, 111-120, and >120
mmHg). These percentages were determined by counting the number of
hours each rat spent in a given MAP range. The total hours in each
specified range (i.e., 12 h MAP <100 mmHg) were then divided by
the total number of hours for a day (i.e., 24 h) to arrive at a
percentage (i.e., 50%).
|
|
View larger version (27K):
[in this window]
[in a new window]
|
Fig. 6.
Pie graphs of 24-h MAP and 12:12-h light-dark averages in
SHR/y caged and colony rats. Each circle represents 100% of time spent
at the ranges of MAP (<100, 100-110, 111-120, and >120
mmHg). An examination of the %time with MAP >120 mmHg shows that
there was a significant strain difference (2-way ANOVA
P = 0.00077); however, there was not a significant
difference among the different housing treatments. The strain effect
does not depend on the particular type of housing, and there was not a
statistically significant interaction between strain and housing.
|
|
Figure 7 shows that SNS blockade with
clonidine significantly reduced both the SHR/y and WKY colony BP
(SHR/y: 2-way ANOVA, P < 0.0001; WKY: 2-way ANOVA,
P < 0.0001). There was a significant difference
comparing strain, treatment, and time (Table
3: 3-way ANOVA: strain P < 0.001; treatment P < 0.001; time P = 0.003). Clonidine reduced both light and dark MAP compared with
control, with the greatest decrease in the dark cycle.
View larger version (26K):
[in this window]
[in a new window]
|
Fig. 7.
Line graph of 24-h MAP at baseline and after clonidine
treatment in WKY and SHR/y colonies. MAP expressed as means ± SE.
Except for the first and last data points, error bars are omitted for
clarity. There was a significant difference comparing strain,
treatment, and time (3-way ANOVA: strain df = 1, F = 79.165, P < 0.001; treatment df = 1, F = 27.777, P < 0.001; time df = 23, F = 1.240, P = 0.206). Clonidine
significantly reduced both WKY (2-way ANOVA: F = 45.85, df = 1, P < 0.0001) and SHR/y MAP (2-way ANOVA:
F = 40.49, df = 1, P < 0.0001)
compared with baseline.
|
|
A comparison of HR showed a clear circadian variation in each strain
(Fig. 8). Although there was no
significant difference in HR between strains or housing, there was a
significant difference between control and clonidine treatment (3-way
ANOVA: strain P = 0.08; treatment P < 0.001; time P < 0.001; WKY: 2-way ANOVA: treatment
P = 0.0001; SHR/y: 2-way ANOVA: treatment
P = 0.0018). Figure 9
shows that HR was attenuated by clonidine during the dark but not the
light cycle in both strains. In both control strains, HR is greater
during the dark compared with the light cycle (WKY P < 0.001; SHR/y P < 0.0001). HR was reduced in both strains by clonidine during the dark cycle (WKY: control dark vs.
clonidine dark, t-test P = 0.0001; SHR/y:
control dark vs. clonidine dark, t-test P = 0.002). There was no significant difference in WKY or SHR/y control
light vs. clonidine light. There was no strain difference in response
to clonidine.
View larger version (29K):
[in this window]
[in a new window]
|
Fig. 8.
Line graph of 24-h heart rate (HR) of WKY and SHR/y in
caged and colony housing (A) and in clonidine-treated
colonies (B). HR expressed as means ± SE. Except for
the first and last data points, error bars are omitted for clarity.
There was no significant difference in HR between strains or housing;
however, there was a significant difference between control and
clonidine treatment after allowing for the effects of differences in
strains and time (3-way ANOVA: strain F = 3.39, df = 1, P = 0.08; treatment F = 96.08, df = 1, P < 0.001; time F = 12.34, df = 23, P < 0.001; WKY: 2-way ANOVA:
treatment F = 27.25, df = 1, P = 0.0001; SHR/y: 2-way ANOVA: treatment F = 12.37, df = 1, P = 0.0018). bpm, Beats/min.
|
|
View larger version (34K):
[in this window]
[in a new window]
|
Fig. 9.
Bar graph of 12-h average HR comparing light and dark
cycles of WKY and SHR/y colony rats at baseline and after clonidine
treatment. HR expressed as means ± SE (3-way ANOVA: strain
F = 3.39, df = 1, P = 0.08;
treatment F = 96.08, df = 1, P < 0.001; cycle F = 12.34, df = 1, P < 0.001). In both control strains, HR is greater during the dark
compared with the light cycle (WKY P < 0.001; SHR/y
P < 0.0001). HR was reduced in both strains by
clonidine during the dark cycle (WKY: control dark vs. clonidine dark,
t-test, *** P = 0.0001; SHR/y: control
dark vs. clonidine dark, t-test, ** P = 0.002). There was no significant difference in WKY or SHR/y control
light vs. clonidine light. There was no strain difference in response
to clonidine.
|
|
Locomotor activity also showed a clear circadian variation in each
strain (Fig. 10). Activity levels in
both strains significantly increased in the colony compared with
individually caged rats (2-way ANOVA: SHR/y P = 0.0007;
WKY P = 0.0057). However, there was no significant
strain difference in activity between the SHR/y colony and WKY colony
or the SHR/y caged and WKY caged. Clonidine increased the colony
activity levels in both strains (2-way ANOVA: SHR/y P < 0.0001; WKY P < 0.0001), but there was no
significant strain difference.
View larger version (27K):
[in this window]
[in a new window]
|
Fig. 10.
Line graph of 24-h activity level by strain and
treatment. Activity is expressed as means ± SE. Except for the
first and last data points, error bars are omitted for clarity.
Activity levels were significantly increased in the WKY (A;
2-way ANOVA: F = 9.29, df = 1, P = 0.0057) and SHR/y (B; 2-way ANOVA: F = 15.29, df = 1, P = 0.0007) colony compared with
individually caged rats. There was no significant strain activity
difference between the SHR and WKY colony or the SHR/y or WKY caged.
Clonidine increased the colony activity levels in both WKY (2-way ANOVA
F = 11.48, df = 1, P < 0.0001)
and SHR/y (2-way ANOVA F = 29.0, df = 1, P < 0.0001) rats, but there was no significant strain
difference.
|
|
| |
DISCUSSION |
A number of studies have previously addressed the advantages of
using implantable radiotelemetry transmitters to examine circadian rhythms of cardiovascular parameters in experimental animals
(5, 47). One clear advantage is that the
telemetric technique permits the continuous monitoring of parameters in
freely moving untethered animals. In addition, cardiovascular and
behavioral parameters can be monitored for extended periods of time
without human intervention. However, to avoid interference between
transmitter signals, rats in most telemetry studies are individually
housed. Our study is one of the first to show that during a 24-h period
BP values obtained from individually caged animals may be lower than BP
obtained from animals socially interacting in a colony environment,
especially notable in the active dark cycle. In addition, a daily BP
average does not accurately represent the extreme fluctuations that can occur from moment to moment during a day as was noted by the 10-mmHg increase in nocturnal MAP of the SHR/y colony. Recently, Otsuka et al.
(33) showed that excessive amplitude of BP over 48 h increased the relative risk for ischemic stroke and nephropathy in humans.
This has implications for both animal and human studies. The use of a
colony system of socially interacting animals mimics a more natural
environment than does individual housing and may permit better
extrapolation to humans who live in a social environment (12, 30, 51). The elegant
studies of Kaplan et al. (22) with primate colonies have
provided strong evidence for the importance of examining cardiovascular
parameters during social interaction. For instance, during the last few
years, there has been an emphasis on human ambulatory BP monitoring
(39, 48), which provides more informative
associations with activity cycles and behavioral patterns. Ambulatory
BP monitoring has documented variations in the diurnal pattern of BP
demonstrating that, in normotensive human subjects and those with
primary hypertension, there was a reduction (dipping) in BP at night
(2, 35). Indeed, the lack of this reduction
during the inactive cycle may be of diagnostic value (36,
37, 40, 48). For instance, in
all renal forms of secondary hypertension and in most endocrine forms,
the nighttime BP reduction is only one-third to one-half of normal
(31). However, in diabetes mellitus hypertensives, there
was no influence on the circadian variation of BP unless autonomic
neuropathy was present (28).
The implications for elevated nighttime BP are that structural
compensations can occur commensurate with the length of time the
pressure remains elevated, and at some point this may become irreversible. Indeed, both WKY and SHR/y had higher nocturnal MAP in
the colony than individually caged rats. For the SHR/y, this was a 30%
increase in MAP >120 mmHg in a 24-h period. With repeated episodes of
social stress, the hypothalamic defense system is activated with
neurohumoral compensations. If the stress is maintained, BP remains
elevated, and vascular structural compensations can occur
(6, 18, 24). After prolonged
hypertension, the structural adaptation can become permanent
(13, 18). Henry et al. (18)
showed that normotensive mice, when stressed through isolation followed
by social interaction for prolonged periods with BP in the range of
140-160 mmHg for 6 mo, have irreversible vascular, cardiac, and
renal pathology. When the social stress from colony interaction was
removed at earlier times (1, 2, and 3 mo), the BP gradually returned to
normal because the permanent structural vascular change had not
occurred. Lawler et al. (24) demonstrated that
psychological stress could potentiate hypertension in borderline
hypertensive rats and that termination of the conflict did not reduce
the hypertension. In addition, these stressed animals compared with
nonstressed controls exhibited elevated heart-to-body weight ratios and
significant cardiac pathology. Von Holst (49) also
demonstrated that chronic social stress in tree shrews produced renal
pathology. In addition, he showed that the percentage of time in a 24-h
period that animals spent in sympathetic activation directly correlated
with the cardiovascular pathology. HR remained elevated at night in the
subdominant animals, and tyrosine hydroxylase in the adrenal gland was
increased 100% (50).
One of the mechanisms that may potentiate the BP of colony animals is
the SNS. The increased social interaction in a colony with competition
for food, females, and territory activates the SNS and neuroendocrine
adaptations (8, 10, 18,
19, 30). Supporting this idea are the colony
studies of cynomolgus monkeys showing that atherosclerosis is
potentiated in individuals who are habitually successful in aggressive
encounters with intruders, and the associated pathology is related in
part to SNS activation (22). Social interaction in a
colony may even intensify autonomic responses to ordinary events like
eating. SHR 15-day-old pups had higher BP responses to feeding than
WKY, and the mechanism appeared to be increased SNS-mediated
vasoconstriction (32). Even brief bouts of conflict with
an intruder in a colony can disrupt the autonomic circadian rhythms for
several weeks and can involve both vagal and sympathetic components
(42).
In this study, both animal strains and both housing treatments showed
higher BP in the dark cycle compared with the light cycle, although not
significantly in the SHR/y individually caged animals. Possibly
of greater importance, however, is that nocturnal MAP increased nearly
three times as much in the SHR/y colony compared with the WKY colony
rats (WKY colony 3.2 mmHg increase; SHR/y 9.5 mmHg increase). Previous
studies in mice (10) and rats (11) showed
that SNS indexes were increased in a colony environment. In addition,
our laboratory has shown that the SHR Y chromosome increases BP through
increased indexes of SNS activity (7, 21). It
appears that sympathetic activity contributes to the higher BP during
the active dark compared with the resting light cycle as shown by the
reduction in nocturnal BP by clonidine (an 
2-adrenoreceptor agonist) in the SHR/y colony. Clonidine
has also been shown to diminish but did not prevent the rise in BP in
Long Evans rats after social defeat (30).
The higher BP and HR levels during the dark compared with the light
cycle are most likely related to the increased level of motor activity
and SNS activity during the dark cycle. However, locomotor activity
alone cannot account for the BP variation since the colony BP continued
to remain elevated for a time after the activity level declined. Also,
there was no difference in activity levels between the WKY and SHR/y
colonies, yet there was a significant nocturnal rise in BP in the SHR/y
colony. In addition, BP decreased with clonidine even though there was
a slight increase in activity. Also, it has been shown that patients in
a vegetative state who lacked a response to external stimuli still had
a circadian rhythm for temperature, hormones, and sodium but not for BP
or HR (15). Otsuka et al. (33) showed that
responses did not appear to show linkage even though during acute
responses like the baroreflex there is an inverse relationship between
the two variables.
In conclusion, our data show that the nocturnal MAP of the SHR/y colony
males is 4 mmHg greater than strain-matched individually caged male
rats and 10 mmHg greater than the WKY colony males. We propose that
this enhanced nocturnal MAP is due to increased SNS activity due to the
Y chromosome effect. The clonidine-induced reduction in nocturnal BP
supports this hypothesis.
We have also demonstrated a SHR Y chromosome BP effect, with the SHR/y
strain in the colony spending 23% of a 24-h period at a MAP >120
mmHg, whereas the WKY strain in the colony spent 2% of a 24-h period
in this range. This suggests that the SHR/y arterial vasculature would
be exposed to higher pressures for longer periods compared with that of
WKY rats. Therefore, structural adaptations (13) and
eventually pathology could occur (18). Ongoing studies are
examining the aorta, coronary and mesenteric arteries, and kidneys for
pathological changes.
| |
ACKNOWLEDGEMENTS |
We appreciate the technical support of Fieke Bryson and Sarah Francis.
| |
FOOTNOTES |
This research was supported National Heart, Lung, and Blood Institute
Grant HL-48072-06 and the Ohio Board of Regents Grant 534540 to the
Hypertension Center, University of Akron.
Address for reprint requests and other correspondence: A. Caplea, Dept. of Biology, The Univ. of Akron, Akron, OH
44325-3908 (E-mail:acaplea{at}uakron.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. §1734 solely to indicate this fact.
Received 30 July 1999; accepted in final form 4 January 2000.
| |
REFERENCES |
1.
Berger, DF,
and
Starzec JJ.
Contracting level-press avoidance behaviors of spontaneously hypertensive and normotensive rats (Rattus norvegicus).
J Comp Psychol
102:
279-286,
1988[Web of Science][Medline].
2.
Bevan, AT,
Honour AJ,
and
Stott FW.
Direct arterial pressure recording in unrestricted man.
Clin Sci (Lond)
36:
329-344,
1969[Web of Science][Medline].
3.
Brown, KJ,
and
Grunberg NE.
Effects of housing on male and female rats: crowding stresses males but makes calm females.
Physiol Behav
58:
1085-1089,
1995[Medline].
4.
Brown, KJ,
and
Grunberg NE.
Effects of environmental conditions of food consumption in female and male rats.
Physiol Behav
60:
293-297,
1996[Medline].
5.
Calhoun, D,
Sutao Zhu J,
Wyss M,
and
Oparil S.
Diurnal blood pressure variation and dietary salt in spontaneously hypertensive rat.
Hypertension
24:
1-7,
1994[Abstract/Free Full Text].
6.
Ely, D.
Hypertension, social rank, and aortic arteriosclerosis in CBA/J mice.
Physiol Behav
26:
655-661,
1981[Medline].
7.
Ely, D,
Caplea A,
Dunphy G,
Daneshvar H,
Turner M,
Milsted A,
and
Takiyyuddin M.
Spontaneously hypertensive rat Y chromosome increases indexes of sympathetic nervous system activity.
Hypertension
29:
613-618,
1997[Abstract/Free Full Text].
8.
Ely, D,
Caplea A,
Dunphy G,
and
Smith D.
Physiological and neuroendocrine correlates of social position in normotensive and hypertensive rat colonies.
Acta Physiol Scand
161, Suppl640:
92-95,
1997[Web of Science].
9.
Ely, D,
Daneshvar H,
Turner M,
Johnson M,
and
Salisbury R.
The hypertensive Y chromosome elevates blood pressure in F11 normotensive rats.
Hypertension
21:
1071-1075,
1993[Abstract/Free Full Text].
10.
Ely, DL,
and
Henry JP.
Neuroendocrine response patterns in dominant and subordinate mice.
Horm Behav
10:
156-169,
1978[Medline].
11.
Ely, DL,
and
Weigand J.
Stress and high sodium effects on blood pressure and brain catecholamines in spontaneously hypertensive rats.
Clin Exp Hypertens
A5:
1559-1587,
1983.
12.
Fokkema, DS,
Koolhaas JM,
and
Van Der Gugten J.
Individual characteristic of behavior, blood pressure, and adrenal hormones in colony rats.
Physiol Behav
57:
857-862,
1995[Medline].
13.
Folkow, B.
Physiological aspects of primary hypertension.
Physiol Rev
62:
347-504,
1982[Free Full Text].
14.
Friberg, P,
Karlsson B,
and
Nordlander M.
Autonomic control of the diurnal variation in arterial blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats.
J Hypertens
7:
799-807,
1989[Web of Science][Medline].
15.
Fukudome, U,
Abe I,
Saku Y,
Matsumura K,
Sadoshima S,
Utunomiya H,
and
Fujishima M.
Circadian blood pressure in patients in a persistent vegetative state.
Am J Physiol Regulatory Integrative Comp Physiol
270:
R1109-R1114,
1996[Abstract/Free Full Text].
16.
Hendley, ED,
Wessel DJ,
and
Van Houten J.
Inbreeding of Wistar-Kyoto rat strain with hyperactivity but without hypertension.
Behav Neural Biol
45:
1-16,
1986[Web of Science][Medline].
17.
Henry, JP,
Liu Y,
Nadra W,
Quan C,
Mormede P,
Lemaire V,
Ely D,
and
Hendley E.
Psychosocial stress can induce chronic hypertension in normotensive strains of rats.
Hypertension
21:
714-723,
1993[Abstract/Free Full Text].
18.
Henry, JP,
Stephens PM,
and
Santisteban GA.
A model of psychosocial hypertension showing reversibility and progression of cardiovascular complications.
Circ Res
36:
156-164,
1975[Abstract/Free Full Text].
19.
Ishikawa, M,
Ohdo S,
Watanabe H,
Hara C,
and
Ogawa N.
Alteration in circadian rhythm of plasma corticosterone in rats following sociopsychological stress induced by communication box.
Physiol Behav
57:
41-47,
1995[Medline].
20.
James, GD,
and
Pickering TG.
The influence of behavioral factors on the daily variation of blood pressure.
Am J Hypertens
6:
170S-173S,
1993[Medline].
21.
Jones, T,
Dunphy G,
Milsted A,
and
Ely D.
Testosterone effects on renal norepinephrine content and release in rats with different Y chromosomes.
Hypertension
32:
880-885,
1998[Abstract/Free Full Text].
22.
Kaplan, JR,
Manuck SB,
Clarkson TB,
Lusso FM,
and
Taub DM.
Social status, environment and atherosclerosis in cynomolgus monkeys.
Arteriosclerosis
2:
359-368,
1982[Abstract/Free Full Text].
23.
Knardahl, S,
and
Sagvolden T.
Open-field behavior of spontaneously hypertensive rats.
Behav Neural Biol
27:
187-200,
1979[Web of Science][Medline].
24.
Lawler, JE,
Barker GF,
Hubbard JW,
and
Schaub RG.
Effects of stress on blood pressure and cardiac pathology in rats with borderline hypertension.
Hypertension
3:
496-505,
1981[Abstract/Free Full Text].
25.
Le Doux, JE,
Sakaguchi A,
and
Reis DJ.
Behaviorally selective cardiovascular hyperreactivity in spontaneously hypertensive rats. Evidence for hypoemotionality and enhanced appetitive activation.
Hypertension
4:
853-863,
1982[Abstract/Free Full Text].
26.
Lyons, DM,
Chae MG,
Levine H,
and
Levine S.
Social effects and circadian rhythms in squirrel monkey pituitary-adrenal activity.
Horm Behav
29:
177-190,
1995[Medline].
27.
Mancia, LG,
Grassi G,
Parati G,
and
Zanchetti H.
The sympathetic nervous system in human hypertension.
Acta Physiol Scand
161, Suppl640:
117-121,
1997.
28.
Matsumura, K,
Abe I,
Tsuchihashi T,
Kobayashi K,
and
Fujishima M.
Circadian variations of blood pressure and pulse rate in essential hypertensives with diabetes mellitus.
Clin Exp Pharmacol Physiol
20:
155-160,
1993[Web of Science][Medline].
29.
McCarty, R,
and
Kopin IJ.
Alterations in plasma catecholamines and behavior during acute stress in spontaneously hypertensive and Wistar-Kyoto normotensive rats.
Life Sci
22:
997-1006,
1978[Web of Science][Medline].
30.
Meehan, WP,
Tornatzky W,
and
Miczek KA.
Blood pressure via telemetry during social confrontations in rats: effects of clonidine.
Physiol Behav
58:
81-88,
1995[Medline].
31.
Middeke, M,
and
Schrader J.
Nocturnal blood pressure in normotensive subjects and those with white coat, primary, and secondary hypertension.
Br Med J
308:
630-632,
1994[Abstract/Free Full Text].
32.
Myers, MM,
and
Scalzo FM.
Blood pressure and heart rate responses of SHR and WKY rat pups during feeding.
Physiol Behav
44:
75-83,
1988[Medline].
33.
Otsuka, K,
Cornelissen G,
Halberg F,
and
Oehlerts G.
Excessive circadian amplitude of blood pressure increases risk of ischemic stroke and nephropathy.
J Med Eng Technol
21:
23-30,
1997[Web of Science][Medline].
34.
Peng, X,
Lang CM,
Drozdowicz CK,
and
Ohlsson-Wilhelm BM.
Effect of cage population density on plasma corticosterone and periphereal lymphocyte populations of laboratory mice.
Lab Anim Sci
23:
302-306,
1989.
35.
Pickering, TG,
Harshfield GA,
Kleinert HD,
Blank S,
and
Laragh JH.
Blood pressure during normal daily activities, sleep and exercise.
JAMA
247:
9892-9896,
1982.
36.
Rizzoni, D,
Muiesan ML,
Montani G,
Zulli R,
Calebich S,
and
Agabiti-Rosei E.
Relationship between initial cardiovascular structural changes and daytime and night-time blood pressure monitoring.
Am J Hypertens
5:
180-186,
1992[Web of Science][Medline].
37.
Roman, MJ,
Pickering TG,
Schwartz JE,
Cavallini MC,
Pini R,
and
Devereux RB.
Is the absence of a normal nocturnal fall in blood pressure (nondipping) associated with cardiovascular target organ damage?
J Hypertens
15:
969-978,
1997[Web of Science][Medline].
38.
Schillaci, G,
Verdecchia P,
Borgioni C,
Ciucci A,
Zampi I,
and
Pattistelli M.
Association between persistent pressure overload and ventricular arrhythmias in essential hypertension.
Hypertension
28:
284-289,
1996[Abstract/Free Full Text].
39.
Staessen, JA,
O'Brien ET,
Amery AK,
Atkins N,
Baumgart P,
De Cort P,
Degaute JP,
Dolenc P,
De Gaudemaris R,
Enström I,
Fagard R,
Gosse P,
Gourlay S,
Hayashi H,
Imai Y,
James G,
Kawaski T,
Dushnir E,
Kuwajima I,
Lindholm L,
Liu L,
Macor F,
Mancia G,
McGrath B,
Middeke M,
Ming J,
Omboni S,
Kuniaka O,
Palatini P,
Parati G,
Peiper C,
Verdecchia P,
Zachariah P,
and
Zhang W.
Ambulatory blood pressure in normotensive and hypertensive subjects: results from an international database.
J Hypertens
12, Suppl7:
S1-S12,
1994.
40.
Suzuki, Y,
Kuwajima I,
Kanemaru A,
Shimosawa T,
Hoshino S,
and
Sakai M.
The cardiac functional reserve in elderly hypertensive patients with abnormal diurnal change in blood pressure.
J Hypertens
10:
173-179,
1992[Web of Science][Medline].
41.
Tonkiss, J,
Trzcinska M,
Galler JR,
Ruiz-Opazo R,
and
Herrera VLM
Prenatal malnutrition-induced changes in blood pressure. Dissociation of stress and nonstress responses using radiotelemetry.
Hypertension
32:
108-114,
1998[Abstract/Free Full Text].
42.
Tornatzky, W,
and
Miczek KA.
Long-term impairment of autonomic circadian rhythms after brief intermittent social stress.
Physiol Behav
53:
983-993,
1993[Medline].
43.
Tucker, DC,
and
Hunt RA.
Effects of long-term air jet noise and dietary sodium chloride in borderline hypertensive rats.
Hypertension
22:
527-534,
1993[Abstract/Free Full Text].
44.
Tucker, DC,
and
Johnson AK.
Behavioral correlates of spontaneous hypertension.
Neurosci Biobehav Rev
5:
463-471,
1981[Web of Science][Medline].
45.
Turner, M,
Johnson M,
and
Ely D.
Separate sex-influenced and genetic components in spontaneously hypertensive rat hypertension.
Hypertension
17:
1097-1103,
1991[Abstract/Free Full Text].
46.
Uzu, T,
Nishimura M,
Jujii T,
Takeji M,
Kuroda S,
Nakamura S,
Inenaga T,
and
Kimura G.
Changes in the circadian rhythm of blood pressure in primary aldosteronism in response to dietary sodium restriction and adrenalectomy.
J Hypertens
16:
1745-1748,
1998[Web of Science][Medline].
47.
Van den Buuse, M.
Circadian rhythms of blood pressure, heart rate, and locomotor activity in spontaneously hypertensive rats as measured with radio-telemetry.
Physiol Behav
55:
783-787,
1994[Medline].
48.
Verdecchia, P,
Porcellati C,
Schillaci G,
Borgioni C,
Ciucci A,
Battistelli M,
Guerrieri M,
Gatteshci C,
Zampi I,
Santucci A,
Santucci C,
and
Reboldi G.
Ambulatory blood pressure an independent predictor of prognosis in essential hypertension.
Hypertension
24:
793-801,
1994[Abstract/Free Full Text].
49.
Von Holst, D.
Renal failure as the cause of death in Tupaia belangeri exposed to persistent social stress.
J Comp Physiol Psychol
78:
236-273,
1972.
50.
Von Holst, D.
Vegetative and somatic components of tree shrew's behavior.
J Auton Nerve Sys
Suppl:
657-670,
1986.
51.
Von Holst, D.
Social relations and their health impact on tree shrews.
Acta Physiol Scand
161, Suppl 640:
77-82,
1997.
Am J Physiol Heart Circ Physiol 279(1):H58-H66
0363-6135/00 $5.00
Copyright © 2000 the American Physiological Society
TOP
ABSTRACT
INTRODUCTION
