Repeated intermittent stress exacerbates
myocardial ischemia-reperfusion injury
DEBORAH A. SCHEUER AND STEVEN W. MIFFLIN
Department of Pharmacology, The University of Texas Health Science Center,
San Antonio, Texas 78284-7764
myocardial infarction; restraint stress; chronic stress; corticosterone; arrhythmia
STRESS HAS BEEN IMPLICATED as a risk factor for increased morbidity and mortality due either to myocardial ischemia or to malignant arrhythmia in the absence of ischemia (8, 11, 12, 14, 15, 20). Correlative
studies in humans have implicated acute episodes of
stress associated with emotional upset or catastrophic
events as triggers for myocardial ischemia (11) and
cardiac arrhythmia (14). In experimental animals, it
has been shown that acute stress decreases the fibrillation threshold of the myocardium (14) and increases
the risk for cardiac arrhythmias associated with myocardial ischemia (21, 23). Controlled laboratory studies
in humans have demonstrated that a single episode of
mental stress can trigger myocardial ischemia, particularly in patients with existing coronary artery disease
(11, 15). Also, patients exhibiting larger increases in
arterial pressure and/or heart rate and more frequent
episodes of myocardial ischemia in response to experimentally induced acute mental stress are reported to
have more frequent episodes of myocardial ischemia in
daily life (2, 12). This suggests that susceptibility to
ischemia in response to acute mental stress is indicative of susceptibility to daily life ischemic episodes,
which can lead to myocardial infarction or sudden
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cardiac death. The evidence that chronic stress increases the risk of ischemic heart disease, including
myocardial infarction, is not as substantial. Most of the
evidence is from epidemiological studies that have
linked chronic stressors such as social isolation, depression, and self-reported stress to increased morbidity
and mortality from ischemic heart disease (8, 11, 20).
Controlled studies to assess the impact of chronic stress
on myocardial ischemia and infarction are lacking.
Therefore, the following experiments were conducted to
test the hypothesis that repeated exposure to stress
increases the severity of infarction resulting from myocardial ischemia-reperfusion injury in rats.
Many experimental protocols have been utilized to
produce chronic stress in rats. In the present experiments, we chose to use repeated restraint stress. This is
a stressor that is primarily psychological, evoking an
escape reaction, although there is a component of
physical stress resulting from the escape effort. In
these experiments, the rats were exposed to a moderate
stress of repeated intermittent restraint for 1–2 h daily
for 8–14 days using two slightly different protocols, one
with a moderate and one with a high degree of predictability. The two different protocols were utilized because it has been reported that the magnitude of stress
produced by a stressor varies inversely with the degree
of predictability of the stressor (16). Chronic stress has
been shown to decrease thymus and increase adrenal
weight (3). Therefore, to provide an index of the efficacy
of the restraint protocol as a chronic stressor, thymus
and adrenal weights were measured at the conclusion
of the experiments.
On the day after the final day of restraint stress, the
animals were anesthetized and a myocardial ischemiareperfusion protocol was performed. Infarct size is a
primary predictor of morbidity and mortality from
myocardial infarction in humans (18). Therefore, in
these experiments, infarct size, quantitated as a percentage of the area at risk, was used as the measure of
severity of infarction. The incidence of life-threatening
arrhythmic episodes during ischemia and/or reperfusion was also measured.
METHODS
General Methods
Successful experiments were performed on 19 male Sprague-Dawley rats purchased from Charles River Laboratories
(Wilmington, MA). Seven additional rats were excluded from
the study. Four were excluded because at the end of the
experiment, the area at risk was found to be insufficiently
large (,18% of the left ventricle), and three were excluded
because the surgical preparation was flawed. The rats were
housed in quiet rooms with a 12:12-h light-dark cycle (7 AM to
0363-6119/98 $5.00 Copyright r 1998 the American Physiological Society
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Scheuer, Deborah A., and Steven W. Mifflin. Repeated
intermittent stress exacerbates myocardial ischemia-reperfusion injury. Am. J. Physiol. 274 (Regulatory Integrative Comp.
Physiol. 43): R470–R475, 1998.—Chronic stress in humans
has been correlated with increased risk for ischemic heart
disease. Thus experiments were conducted to determine if
repeated intermittent restraint stress increased infarct size
in a rat model of myocardial ischemia-reperfusion injury.
Male Sprague-Dawley rats were subjected to no stress (control) or to daily restraint stress for 1–1.5 h for 8–14 days
(stress protocol A) or for 2 h daily for 11 or 12 days (stress
protocol B). Myocardial ischemia-reperfusion (30-min ischemia, 3-h reperfusion) was performed in anesthetized rats.
Average baseline arterial pressures were 111 6 4, 120 6 10,
and 125 6 7 mmHg in the control, stress protocol A, and
stress protocol B groups, respectively. Infarct size (%area at
risk) was significantly larger in both groups of stressed rats
compared with control rats (58 6 5, 78 6 2, and 79 6 3% in
the control, stress protocol A, and stress protocol B groups,
respectively). During ischemia or early reperfusion, zero of
eight control, two of six protocol A stress, and two of five
protocol B stress rats had at least one period of severe
arrhythmia. Therefore, these results provide experimental
evidence corroborating correlative studies in humans that
link chronic stress with increased morbidity and mortality
from ischemic heart disease.
REPEATED INTERMITTENT STRESS INCREASES INFARCT SIZE
7 PM) in a fully accredited (American Association for Accreditation of Laboratory Animal Care and United States Department of Agriculture) laboratory animal care facility at the
University of Texas Health Science Center in San Antonio.
Normal-sodium rat chow and water were available ad libitum. The experimental protocol was approved by the Institutional Animal Care and Use Committee.
Repeated Restraint Stress
Surgical Preparation
On the day of the experiment, rats were anesthetized with
the long-acting rodent anesthetic thiobarbital sodium (Inactin, Research Biomedicals) at an initial intraperitoneal dose
of 110 mg/kg. Supplemental anesthetic was given in intraperitoneal doses of 10 mg/kg as required to maintain a plane of
anesthesia in which there was an absence of withdrawal to
pinch of the hindpaw and no evidence of fluctuations in blood
pressure in response to surgical manipulation. Body temperature was maintained at 36–38°C with a ventral heating pad
and, when required, a dorsal infrared lamp. The animal was
intubated through a tracheotomy and ventilated with room
air that was supplemented with 100% O2. Catheters constructed of PE-50 or microbore Tygon tubing (0.03 in. OD)
were placed in a femoral artery and vein for withdrawal of
blood samples and administration of drugs. The muscle
relaxant pancuronium bromide (0.5 mg · kg21 · h21 ) was infused through the venous catheter throughout the experimental protocol. An additional catheter was introduced into the
right carotid artery and advanced (,3.5–4.0 cm) to the root of
the aorta for measurement of arterial pressure. The animals
were prepared for the myocardial ischemia-reperfusion protocol as previously described (17). A left thoracotomy was made
at the third or fourth intercostal space. The lungs were
retracted, and the pericardium was teased open to expose the
heart. To position a loose ligature around a branch of the left
main coronary artery, a stitch was placed in the left ventricular myocardium, between the origin of the left atrial appendage and the sulcus marking the ventricular septum. Ties were
placed around either side of the suture that passed through
the myocardium. The ties were subsequently used to loosen
the suture to allow for easy reperfusion of the myocardium.
Experimental Protocol
The experimental protocol was initiated 30 min after
completion of the surgical procedures to allow for stabilization of hormonal and cardiovascular variables. The protocol
was a total of 4 h long, consisting of a 30-min baseline period,
a 30-min period of myocardial ischemia, and a 3-h period of
reperfusion. To produce ischemia, the ligature around the
coronary artery was tied tightly, and the ends of the suture
were placed through a piece of tubing which was used to keep
the ligature closed and to provide an additional means of
occluding the vessel. At the end of the experiment, the
coronary artery was reoccluded and the heart was perfused
with Unisperse Blue dye (Ciba-Geigy, Newport, DE) through
the left ventricular catheter. This procedure delineated the
area at risk, which is defined as the portion of the myocardium perfused by the occluded vessel. The animal was then
killed with an overdose of pentobarbital sodium (100 mg/kg
iv), and the heart was quickly removed. Chronic stress can
decrease thymus weight and increase adrenal weight (3).
Therefore, the adrenal and thymus glands were also removed,
and their weights were used as indexes of the physiological
efficacy of the repeated restraint stress protocol. The adrenals
were not weighed in one control and one stress protocol A rat,
and the thymus was not weighed in two control rats and one
stress protocol A rat.
Experimental groups. Experiments were performed in three
groups of rats. Group 1 consisted of unstressed, control rats
(n 5 8). Group 2 consisted of the rats subjected to the shorter
but less predictable restraint protocol (stress protocol A, n 5
6), whereas group 3 consisted of rats subjected to the invariant 2-h stress protocol (stress protocol B, n 5 5). Rats in group
1 were housed separately from those in groups 2 and 3 to
minimize disturbance of the control rats. The control rats
were not handled every day but were subject to the normal
handling associated with usual animal care. Normal care
includes, but is not limited to, a complete cage change at least
twice a week and a change of water bottles three times a
week. The daily handling of the stressed rats required to
place them in and remove them from the restraint devices
was therefore considered to be part of the repeated-stress
protocol.
Cardiovascular data. Arterial pressure was measured from
the carotid arterial catheter using a pressure transducer
(Cobe Cardiovascular, Arvada, CO) and a transducer coupler
(Coulbourn Instruments, Allentown, PA). Mean arterial pressure (MAP) and heart rate were determined from pulsatile
pressure using a Coulbourn blood pressure processor. Cardiovascular data were collected using MacLab (ADInstruments,
Castle Hill, Australia) or Cambridge Electronic Design (Cambridge, UK) analog-to-digital converters connected to Macintosh or IBM clone computers. Heart rate values were unavailable for one control rat.
Measurement of infarct and risk areas. After the heart was
excised from the animal, the left ventricle was sliced into four
to five transverse slices 2- to 3-mm thick and stained with 1%
triphenyl tetrazolium chloride (TTC). TTC stains viable tissue red, and the necrotic portions of the myocardium become
white (22). Both sides of each slice were imaged (Optimus,
BioScan, Edmonds, WA) to determine the total area, area at
risk, and area of infarct for each slice. Each slice was then
weighed. The total area, area at risk, and area of infarct were
calculated for the entire left ventricle based on the areas and
weight determined for each slice. The total area at risk was
quantitated as a percentage of the left ventricle, and the area
of infarct was quantitated as a percentage of the area at risk.
On the basis of previous experience, we set 18% as the
minimum acceptable area at risk, because with an area at
risk smaller than this, there is frequently little or no infarct
in control rats (17).
Plasma corticosterone concentration. In some experiments,
arterial blood samples (<100 µl) for the measurement of
plasma corticosterone concentration were obtained during
the baseline period, at the end of the ischemia period, and 1
and 3 h after the initiation of reperfusion. All blood samples
were placed in EDTA-coated microcentrifuge tubes and centrifuged at 4°C. The plasma was removed and kept frozen until
analysis. The plasma corticosterone concentration in each
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To produce chronic intermittent stress, rats were restrained in rodent restraining devices (Fisher Scientific, Fair
Lawn, NJ). The restraint period was usually started within 2
h of lights on, when plasma corticosterone is at the nadir of its
diurnal rhythm and the corticosterone response to stress is
most robust (3). Occasionally the restraint was initiated later,
but always before 11 AM. Two protocols were used. In stress
protocol A, rats were subjected to restraint stress for a
randomly varying duration of 1–1.5 h for 8–14 consecutive
days (averaging 12 6 1 days). In stress protocol B, rats were
always restrained for exactly 2 h for 11 or 12 consecutive
days. Rats were not subjected to restraint stress on the
morning of the experiment.
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REPEATED INTERMITTENT STRESS INCREASES INFARCT SIZE
sample was determined in duplicate or triplicate by radioimmunoassay using a commercially available kit (ImmuChem
double antibody B 125I radioimmunoassay kit; ICN Pharmaceuticals, Costa Mesa, CA). Interassay and intra-assay coefficients of variation are ,11% for all sample pools. Crossreactivity of the antiserum at 50% displacement of
corticosterone is #0.05% for aldosterone, progesterone, and
cortisol.
Data Analysis
RESULTS
Experiments were performed 9–15 days after initiation of the daily restraint stress and in control rats. On
the day of the ischemia-reperfusion experiment, rats
that had been subjected to stress protocol B weighed
less (369 6 6 g, P , 0.05) than rats subjected to stress
protocol A (426 6 11 g) or control rats (420 6 15 g).
Chronic stress has been shown to decrease thymus
weight and increase adrenal weight (3). In the present
studies, thymus weight, measured as grams of thymus
weight per kilogram of body weight, was significantly
reduced in both groups of stressed rats compared with
control rats, indicating that the protocols used were
effective in producing chronic stress (Fig. 1). However,
adrenal weights were not different among the groups
(Fig. 1).
Figure 2 shows the average MAP for each experimental time period (baseline, ischemia, and reperfusion) for
all three groups of rats. Although there was a tendency
for stress to increase baseline MAP, the differences
among the groups were not significant. Average baseline arterial pressures were 111 6 4, 120 6 10, and
Fig. 1. Average thymus (A) and adrenal (B) weights in
control rats and rats subjected to stress protocols A and
B. Weights are expressed as mg tissue/kg body wt.
Thymus weights were significantly decreased by both
stress protocols. * P , 0.05 relative to control group.
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Data were analyzed using MacLab (ADInstruments),
Spike2 (Cambridge Electronic Design), and SuperANOVA
(Abacus Concepts, Berkeley, CA) software. Continuous measurements of arterial pressure and heart rate were averaged
over each experimental time period (30 min of control, 30 min
of ischemia, and 3 h of reperfusion) and were analyzed using
analysis of variance (ANOVA). Additional analyses were
performed on these data averaged into 2-min bins. Area at
risk as a percentage of the left ventricle and area of infarct as
a percentage of area at risk were analyzed by ANOVA after
arcsin transformation. Body weight, adrenal and thymus
weights (mg/kg body wt), and plasma corticosterone concentrations were also analyzed by ANOVA. Average values are
reported as means 6 SE. Post hoc analyses were performed
using Fisher’s protected least-significant differences test.
Results were considered significant at P # 0.05.
125 6 7 mmHg in the control, stress protocol A, and
stress protocol B groups, respectively. In control rats,
there was no significant change in arterial pressure
during ischemia or reperfusion. In contrast, arterial
pressure fell significantly during reperfusion in the
both the stress protocol A and B groups. As with MAP,
baseline heart rate was not different among the experimental groups (Fig. 3A). Analyzed by two-way ANOVA,
heart rate increased significantly during ischemia,
with no significant difference between groups. To better
illustrate the effect of ischemia on heart rate, the time
course of the increase in heart rate in response to
ischemia in the individual experimental groups is
illustrated in Fig. 3B. Analyzed by one-way repeatedmeasures ANOVA, heart rate was significantly elevated above baseline throughout the first 10 min of
ischemia (t 5 2 through t 5 10 min) in the stress
protocol B group, and at t 5 4, 6, and 10 min in the
control group. By this method of analysis, there were no
significant increases in heart rate in the stress protocol
A group. All the increases in heart rate in response to
ischemia were transient, and heart rate returned to
baseline by the end of the 30-min period of ischemia.
Plasma corticosterone was measured in four control
and five stress protocol B rats. Baseline plasma corticosterone concentration was not significantly different in
these two groups of rats, averaging 52 6 6 and 44 6 2
µg/dl in control (n 5 4) and stress protocol B rats (n 5
5), respectively. In response to ischemia and reperfusion, plasma corticosterone concentration tended to
increase in the stressed rats and decrease in the control
rats (Fig. 4). Although the changes in corticosterone
from baseline were not significant for either group of
animals, plasma corticosterone increased significantly
during ischemia-reperfusion in the stressed rats relative to the control rats.
Area at risk was defined as the %left ventricle
perfused by the occluded artery. Area at risk, which was
dependent on the exact placement of the ligature and
the anatomy of the coronary arteries in each rat, was
not different among the groups (Fig. 5A). In all experiments, the area at risk was largely or completely in the
anterior portion of the left ventricular myocardium.
Area of infarct was defined as the percentage of the
area at risk that was no longer viable, as indicated by
the TTC staining of the myocardium at the conclusion
of the experiment. Rats from both chronic intermittent
REPEATED INTERMITTENT STRESS INCREASES INFARCT SIZE
weights were used to indicate the efficacy of the stress
protocol (3). Thymus weight was significantly reduced
in both groups of stressed rats, indicating that both
stress protocols successfully actualized chronic stress.
Chronic stress did not increase adrenal weight in these
experiments, suggesting that the magnitude of stress
produced by these protocols was not severe. In some
studies, chronic stress has also been reported to increase baseline MAP (7) and increase the glucocorticoid
response to a novel stressor (3). In the present experiments there was a tendency for baseline arterial pressure to be increased in the chronically stressed rats,
although the increase was not statistically significant.
This is in agreement with other studies reporting that
mild or moderate chronic stress is not sufficient to
produce hypertension in normal laboratory animals (6).
In the present experiments, the corticosterone response
to ischemia-reperfusion was measured in some of the
rats. Although the changes in corticosterone from baseline were not significant for either group of animals,
plasma corticosterone increased significantly during
stress protocols had significantly larger areas of infarct
than did the control rats (Fig. 5B). Average areas of
infarction were 58 6 5, 78 6 2, and 79 6 3% in the
control, stress protocol A, and stress protocol B groups,
respectively. During ischemia or early reperfusion, two
of six rats in the protocol A stress group and two of five
rats in the protocol B stress group had at least one
period of severe arrhythmia accompanied by severe
hypotension (MAP #40 mmHg). Normal sinus rhythm
and arterial pressure were reestablished by gently
tapping or stroking the heart with a cotton swab. No
similar episodes of severe arrhythmia requiring intervention were observed in the control rats. One rat in
the protocol A stress group was killed 25 min early due
to an additional episode of arrhythmia that produced
intractable hypotension.
DISCUSSION
There are many clinical reports that suggest that
exposure to excessive stress correlates with increased
morbidity and mortality from cardiovascular diseases,
including myocardial ischemia (8, 11, 12, 14, 15, 20).
The primary finding of this study is that daily exposure
of rats to 8–14 days of 1–2 h of restraint stress
increased the size of infarction resulting from ischemiareperfusion injury. Because the animals were not restrained on the day of the experiment, the increased
infarct size was not due to an acute episode of stress
experienced just before ischemia-reperfusion. Patients
with myocardial ischemia can suffer fatal arrhythmias,
a cause of mortality termed ‘‘sudden cardiac death’’
(11). In the present study, it was observed that rats
subjected to the repeated stress had a higher incidence
of potentially fatal arrythmias. Therefore, the results
from this study suggest that repeated exposure to
stress influences the outcome of an episode of myocardial ischemia both by increasing infarct size and by
increasing the incidence of fatal arrhythmia.
Repeated restraint was used to produce chronic
stress in the present studies, and adrenal and thymus
Fig. 3. A: average heart rate [beats/min (bpm)] during the baseline
(solid bars), ischemia (crosshatched bars), and reperfusion (hatched
bars) experimental periods. Data are shown for rats in control, stress
protocol A, and stress protocol B groups. * P , 0.05 relative to
baseline period analyzed by 2-factor analysis of variance. B: detailed
illustration of average heart rate during 30-min period of ischemia
and first 30 min of reperfusion. Data are shown for control (solid line),
stress protocol A (dotted line), and stress protocol B (dashed line).
* P , 0.05 relative to baseline value for that group. Heart rate
increased significantly at time 5 2, 4, 6, 8, and 10 min of ischemia in
the stress protocol B group and at 4, 6, and 10 min in the control
group. Increase in heart rate during ischemia in stress protocol A
group was not statistically significant. However, there was no statistical difference in values for heart rate among the 3 experimental
groups.
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Fig. 2. Average mean arterial pressure during the baseline (solid
bars), ischemia (crosshatched bars), and reperfusion (hatched bars)
experimental periods. Data are shown for rats in control, stress
protocol A, and stress protocol B groups. * P , 0.05 relative to
baseline period; ** P , 0.05 relative to baseline and ischemia periods.
Thus in the stress protocol A group, pressure decreased significantly
from baseline during reperfusion. In the stress protocol B group,
pressure during reperfusion was decreased significantly relative to
both baseline and ischemia periods.
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REPEATED INTERMITTENT STRESS INCREASES INFARCT SIZE
ischemia-reperfusion in the stressed rats relative to the
control rats. The corticosterone response in the stressed
rats could have been due directly to the chronic stress
or due to the greater myocardial damage in the stressed
rats. All the results, taken together, indicate that the
repeated intermittent stress protocols used in this
study produced only a moderate degree of chronic stress.
It has been reported that the magnitude of stress
produced by a stressor varies inversely with the degree
Fig. 5. Average area at risk [as %left ventricle (LV); A] and average
infarct (as %area at risk; B). Data are shown for rats in control, stress
protocol A, and stress protocol B groups. * P , 0.05 relative to control
group. Infarct size was significantly increased in both groups of
stressed rats.
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Fig. 4. Average change in plasma corticosterone (Cort) from baseline
period at end of 30 min of ischemia and after 1 and 3 h of reperfusion
in 4 control rats (j) and 5 stress protocol B rats (r). * Corticosterone
responses to ischemia and reperfusion were significantly different
between the 2 groups of rats (P , 0.05).
of predictability of the stressor (16). Two slightly different stress protocols were used. Stress protocol A was of
shorter but less predictable duration (varying randomly between 1 and 1.5 h), whereas stress protocol B
was longer in duration but highly predictable (always 2
h). The first group of rats was stressed for a somewhat
unpredictable length of time to minimize desensitization due to the predictability of the stress. The second
group of rats was stressed for exactly 2 h so that the
protocol was completely reproducible from day to day
and rat to rat. We thought it possible that without the
element of unpredictability the restraint stress might
not be sufficient to increase infarct size, and we wanted
to investigate this possibility. Subtle differences between these two groups of rats were observed in the
cardiovascular responses to myocardial ischemia. During ischemia, the stress protocol B group responded
with a significant increase in heart rate (Fig. 3B),
whereas the stress protocol A group did not. During
reperfusion, the MAP fell significantly relative to baseline in the stress protocol A group. In the stress protocol
B group, the reduction in MAP during reperfusion was
significant relative to both the baseline and the ischemia periods. On the day of the ischemia experiment,
body weight was significantly reduced in the protocol B
stressed rats relative to the control and protocol A
stressed rats. However, body weight changes over the
course of the repeated stress and control protocols were
not determined. Although the rats were purchased to
be within the same weight range, the differences in
body weight on the day of the experiment should not be
used as conclusive evidence regarding the severity of
the stress. On the basis of the cardiovascular data,
infarct size, and incidence of arrhythmia, there were no
obvious differences in the two stress paradigms.
Numerous mechanisms could contribute to the effect
of repeated intermittent stress to increase infarct size.
These mechanisms can be divided into two categories.
First, chronic restraint stress could produce anatomical
or physiological changes which predispose the myocardium to increased damage during episodes of ischemiareperfusion. For example, stress alone has been shown
to produce small areas of myocardial necrosis (14). The
elevations in corticosterone that accompany chronic
stress could also contribute to the increased myocardial
necrosis observed in the stressed rats (17). Second, the
repeated restraint stress could alter the physiological
response to the novel acute stress of myocardial ischemia. Stress evokes a number of responses that could
impact the development of ischemia-reperfusion injury.
Some of these responses are protective, such as stimulation of antioxidant mechanisms and increasing the
number of adenosine receptors (14). Detrimental responses include activation of the sympathetic nervous
system (5, 10), increases in angiotensin (5, 19), and
increases in platelet aggregation and blood viscosity
(11). For example, abundant evidence implicates increases in sympathetic nerve activity in the pathogenesis of myocardial ischemia and cardiac arrhythmia (5,
13). Elevations in sympathetic nerve activity can increase myocardial oxygen demand and decrease oxygen
supply and can decrease the electrical threshold for
REPEATED INTERMITTENT STRESS INCREASES INFARCT SIZE
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Perspectives
The results presented here reinforce the concept that
moderate increases in daily life stress, even when
predictable, can increase the risk of morbidity and
mortality from ischemic heart disease. Although clinical studies have demonstrated that stress-reduction
programs are a valuable addition to postinfarction
therapy in humans (15), stress reduction is not routinely incorporated into patient therapy. Studies like
the present one could bolster the case for inclusion of
such stress-reduction programs. Additionally, future
elucidation of the mechanisms involved in stressinduced exacerbation of myocardial injury could indicate effective avenues for preventative pharmaceutical
therapies.
The authors thank Melissa Vitela, Myrna Herrera-Rosales, and
Andrew Suhrbier for excellent technical assistance.
This work was supported by the Texas Affiliate of the American
Heart Association and National Heart, Lung, and Blood Institute
Grant HL-41894.
Address for reprint requests: D. A. Scheuer, Dept. of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl
Drive, San Antonio, TX 78284-7764.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Received 25 June 1997; accepted in final form 6 November 1997.
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arrhythmias (11, 14). Adaptation to repeated stress has
been demonstrated for some responses to acute stress,
such as the stimulation of the sympathetic nervous
system and the hypothalamic-pituitary-adrenal axis (1,
10). However, this adaptation is stressor specific, and
chronic stress has been reported to facilitate some
responses to acute stress, particularly if the stressor is
novel (3, 4, 9). Therefore, chronic stress could potentiate the increases in sympathetic nervous system activity, angiotensin, or other detrimental factors that are
activated during myocardial ischemia-reperfusion.
Clearly, a number of experiments will be required to
sort out the mechanism of the stress-induced exacerbation of myocardial ischemia-reperfusion injury.
In summary, the results from this study demonstrate
that 1–2 h of daily restraint stress for 8–14 days
increased the size of the infarction resulting from
ischemia-reperfusion injury. The repeated exposure to
stress before ischemia-reperfusion also increased the
incidence of severe arrhythmia. The degree of stress
produced by the intermittent restraint stress protocol
can be classified as moderate, because thymus weight
was decreased but adrenal weights and baseline arterial pressure were not increased by the stress protocols.
Even when the stressor was highly predictable, infarct
size and arrhythmia incidence were increased. Therefore, these results provide experimental evidence corroborating correlative studies in humans that link
chronic stress with increased morbidity and mortality
from ischemic heart disease.
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