© 1997 American Heart Association, Inc.
Articles |
Evidence That Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Is Triggered by the Generation of Nitric Oxide
From the Experimental Research Laboratory, Division of Cardiology, University of Louisville (Ky).
Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail rObollO1{at}ulkyvm.louisville.edu
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Abstract |
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Abstract Recent studies in conscious pigs and rabbits have demonstrated that a series of brief coronary occlusions renders the heart relatively resistant to myocardial "stunning" 24 hours later (late preconditioning [PC] against stunning). The mechanism of this powerful cardioprotective response is unknown. The goal of the present study was to test the hypothesis that the development of late PC against stunning is triggered by increased generation of NO during the first ischemic challenge. Conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3). On day 1, rabbits received either an intravenous infusion of the NO synthase inhibitor N
-nitro-L-arginine (L-NA, 13
mg/kg before the first occlusion) (group II, n=10) or vehicle (group I
[control], n=10). In the control group, on day 1 systolic
wall thickening (WTh) in the ischemic/reperfused region
remained significantly depressed for 4 hours after the sixth
reperfusion, indicating myocardial stunning. On days 2 and 3, however,
the recovery of WTh improved markedly, so that the total deficit of WTh
decreased by 60% on day 2 and 55% on day 3 compared with day 1
(P<.01). In the L-NA–treated group, the total deficit of
WTh on day 1 was similar to that observed in the control group. On day
2, however, the total deficit of WTh was not significantly different
from that observed on day 1 and was 132% greater than that observed in
control rabbits on day 2 (P<.01). On day 3, the total
deficit of WTh was 66% less than that noted on day 2
(P<.01). Thus, in L-NA–treated rabbits the sequence of six
coronary occlusions and reperfusions performed on day 1 failed
to precondition against stunning on day 2, but the same sequence
performed on day 2 did precondition against stunning on day 3. Another
group of rabbits (group III, n=6) received L-NA on day 1 in the absence
of ischemia and was subjected to the occlusion/reperfusion
sequence on days 2 and 3. In these animals, the total deficit of WTh on
day 2 did not differ from that observed in control rabbits on day 1,
indicating that administration of L-NA did not exacerbate the severity
of myocardial stunning 24 hours later; therefore, the absence of late
PC against stunning on day 2 in group II cannot be ascribed to a
delayed deleterious action of L-NA on WTh. In conclusion, these results
demonstrate that the NO synthase inhibitor L-NA completely
blocks the development of late PC against myocardial stunning in
conscious rabbits, indicating that NO generated as a result of the PC
ischemia triggers the development of the cardioprotective
response observed 24 hours later. NO is known to exert numerous
biological actions resulting in rapid but transient
physiological responses. The present
observations support a novel pathophysiological
paradigm in which NO also plays a key role in the delayed myocardial
adaptations to ischemic stress, acting as a signaling step in
the transduction pathway that leads to increased resistance to
subsequent ischemic injury.
Key Words: L-arginine • nitric oxide synthase • nitrogen radicals • oxygen radicals • myocardial ischemia/reperfusion
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies indicate that in addition to its early protective effects,1 2 3 4 5 6 7 8 ischemic PC elicits a second or late phase of protection against myocardial infarction9 10 11 12 and myocardial stunning.13 14 15 16 17 18 19 20 Relatively little is known regarding the mechanism of the late phase of PC. In previous studies,15 we found that administration of antioxidant therapy [superoxide dismutase plus catalase plus N-(2-mercaptopropionyl)-glycine] during the PC ischemia completely prevented late PC against myocardial stunning, indicating that the development of the protection is mediated by the generation of ROS during the initial ischemic stimulus. However, the exact nature of the ROS responsible for triggering the late protective effect, as well as the mechanism(s) leading to their formation, remains unknown.
One of the species that could contribute to enhanced ROS generation and
oxidative stress during myocardial ischemia and reperfusion is
NO.21 22 Endothelial cells produce NO
under basal conditions via a constitutively expressed,
calcium-activated, NADPH-dependent NOS that oxidizes
L-arginine.22 23 Reperfusion following
transient ischemia could stimulate rapid NO synthesis by
providing the oxygen needed to produce NO, since calcium and NADPH have
already been made available by the ischemic
insult.24 25 At the same time, endothelial
production of superoxide anion
(
O2-) is also accelerated in the early
phase of reperfusion.24 26 27 Beckman and
colleagues25 28 have shown that
O2- and NO react rapidly to form the
peroxynitrite anion (ONOO-), which then protonates and
decomposes to generate the hydroxyl radical (OH) or some other
potent oxidant with similar reactivity. NO also reacts with lipophilic
peroxyl radicals to generate alkyl peroxynitrates
(LOONO).21 Based on these facts, it appears plausible to
postulate that reperfusion may be associated with a burst of NO
generation, which could be an important mechanism of formation of
ONOO-, OH, and other secondary reactive species,
with consequent oxidative stress. This concept is supported by a number
of studies demonstrating increased formation of NO and/or
ONOO- in piglet hearts during hypoxia and
reoxygenation,29 in rat and dog hearts
during ischemia and/or immediately after
reperfusion,27 30 31 32 33 in human hearts after cross-clamp
release during cardiac surgery,34 and in various organs
subjected to ischemia/reperfusion
protocols.35 36 37
The goal of the present investigation was to test the hypothesis that the development of late PC against myocardial stunning is triggered by increased generation of NO (and its reactive byproducts) during the initial episodes of ischemia/reperfusion. To this end, we examined whether administration of the NOS inhibitor L-NA during the PC ischemia blocks the development of protection against stunning 24 hours later in conscious rabbits. L-NA was selected because it has been demonstrated to inhibit endothelium-dependent vasodilation in various vascular beds,38 39 40 41 is reported to be more potent than other arginine analogues,38 42 43 and, unlike L-NAME, is devoid of muscarinic receptor antagonism.44 Particular care was taken to select a dose of L-NA that would inhibit increases in NO synthesis while avoiding arterial hypertension, as this effect would complicate the assessment of postischemic contractile function. A PC protocol (six 4-minute coronary occlusions) that has previously been established to induce potent and reproducible protection against myocardial stunning 24 hours later13 17 18 19 20 was used. The study was conducted in conscious rabbits to obviate the confounding effects of factors associated with open-chest preparations, such as anesthesia, surgical trauma, fluctuations in temperature, elevated catecholamines, excessive free radical formation, and cytokine release, which could interfere with myocardial stunning45 46 47 or with PC.7 8
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study was performed in accordance with the guidelines of the Animal Care and Use Committee of the University of Louisville (Ky) School of Medicine and with the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services, Publication No. [NIH] 86-23).
Pilot Studies
Pilot studies were conducted in five rabbits to determine the
optimal dose of L-NA. Since the stunned myocardium is
sensitive to changes in afterload,47 a dosage of L-NA was
sought that would be effective in blocking acetylcholine-induced
vasodilation yet would have no appreciable effect on
arterial blood pressure. In one rabbit, a dose of L-NA of
40 mg/min was infused intravenously over 10 minutes. Before
and after L-NA infusion, endothelium-dependent
vasodilation was tested with intravenous boluses of
acetylcholine. Arterial pressure was measured by
cannulating the ear dorsal artery with a 24-gauge angiocatheter under
local anesthesia (benzocaine). The catheter was connected
to a fluid-filled high-sensitivity pressure transducer, which was
connected to a pressure analyzer (model BPA-109, Micro-Med).
Although this dose of L-NA blunted acetylcholine-induced vasodilation,
it also produced a sustained increase in blood pressure (mean
arterial pressure rose from 61 mm Hg before L-NA to
83 mm Hg 1 hour after L-NA and 80 mm Hg 4 hours after
L-NA). We tested two lower doses of L-NA but found that both were
associated with an increase in blood pressure (30 mg/kg, from 66 to
87 mm Hg at 1 hour after L-NA; 20 mg/kg, from 70 to 77
mm Hg at 1 hour after L-NA in one rabbit and from 68 to 83 mm Hg
in another rabbit). With a dose of 15 mg/kg, mean arterial
pressure rose from 65 to 70 mm Hg at 1 hour and to 70 mm Hg
at 4 hours after L-NA. Although this increase may have been unrelated
to L-NA, when we decreased the dose of L-NA to 13 mg/kg (given
intravenously over 10 minutes), we found that this dose
produced no demonstrable alterations of arterial pressure
but markedly suppressed the endothelium-dependent
vasodilation induced by acetylcholine (see "Results").
Apparently, this is the highest dose that can be administered to
conscious rabbits without causing an increase in blood pressure. This
dose has been previously shown to inhibit NOS activity by
>70%48 and to markedly decrease exhaled NO (measured by
chemiluminescence) in rabbits.49 Consequently, this dose
was chosen for the present experiments.
Experimental Preparation
New Zealand White male rabbits (weight, 2.1± 0.1 kg; age, 3 to
4 months) were anesthetized with sodium methohexital (20 mg/kg
IV), intubated with an endotracheal tube, and mechanically ventilated
with air enriched with oxygen with a positive pressure respirator
(Harvard Apparatus rodent ventilator, model 683).
Anesthesia was maintained with sodium pentobarbital (35
mg/kg IV). Under sterile conditions, the heart was exposed through a
left thoracotomy in the fourth intercostal space. After opening the
pericardium, a balloon occluder was placed around a major branch of the
left coronary artery coursing on the anterior LV wall. The
occluder is a modification of that described by Cohen et
al.7 It is fashioned from 18-gauge Tygon tubing and is
secured to the LV wall with one 3-0 silk suture passing beneath the
coronary artery. Proper function of the occluder was confirmed
by noting cyanosis of the distal myocardium upon inflation
of the balloon and hyperemia after deflation. To measure LV
WTh, a 10-MHz pulsed Doppler ultrasonic crystal50 was
sutured to the epicardial surface in the center of the region to be
rendered ischemic with four 6-0 prolene stitches. A bipolar
lead was anchored to the chest wall to record the ECG. The wires
and the occluder tubing were tunneled under the skin and exteriorized
through small incisions between the scapulae. The chest wound was
closed in layers, and a small tube was left in the thorax for 3 days to
evacuate air and fluids postoperatively. Gentamicin was administered
before surgery and on the first and second postoperative days (0.7
mg/kg IM each day). Rabbits were allowed to recover for a minimum of 10
days after surgery.
Experimental Protocol
Throughout the experiments, rabbits were kept in a cage in a
quiet dimly lit room. LV systolic WTh, range-gate depth, and
the ECG were continuously recorded on a thermal array chart
recorder (Gould TA6000). No sedative or antiarrhythmic agents were
given at any time. The experimental protocol consisted of 3 consecutive
days of coronary artery occlusions (days 1, 2, and 3) (Fig 1
). On each day, the rabbits underwent a sequence of six
4-minute coronary occlusions interspersed with 4 minutes of
reperfusion. The performance of successful coronary
occlusions was verified by observing the development of ST-segment
elevation and changes in the QRS complex on the ECG, and the appearance
of paradoxical systolic wall thinning on the ultrasonic crystal
recordings. Measurements of systolic WTh were obtained
before treatment, 1 minute before the first coronary occlusion,
3 minutes into each occlusion, 3 minutes into each reperfusion period,
and 5, 15, and 30 minutes and 1, 2, 3, 4 and 5 hours after the sixth
reperfusion.
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Rabbits were assigned to three groups: group I (control), group II
(L-NA treatment), and group III (L-NA pretreatment) (Fig 1
). On day 1,
rabbits in group II underwent the six coronary
occlusion/reperfusion cycles and received an intravenous
infusion of L-NA at a rate of 1.3
mg · kg-1 · min-1
for 10 minutes, starting 20 minutes before and ending 10 minutes before
the first coronary occlusion (total dose, 13 mg/kg). L-NA
(Sigma Chemical Co) was dissolved in normal saline (total volume
infused, 20 mL). The solution of L-NA was filtered through a 0.2-µm
Millipore filter to ensure sterility. On days 2 and 3, these rabbits
underwent the same coronary occlusion/reperfusion protocol
without any treatment. In group III, rabbits were treated on day 1 with
the same dose of L-NA but did not undergo coronary occlusion;
these animals were then subjected to the coronary
occlusion/reperfusion protocol on days 2 and 3. Group I (control
rabbits) underwent the coronary occlusion/reperfusion protocol
on days 1, 2, and 3; on day 1, these animals received normal saline
intravenously in volumes equivalent to those administered
to groups II and III (2 mL/min for 10 minutes).
Measurement of Regional Myocardial Function
Regional myocardial function was assessed as
systolic thickening fraction by using the pulsed Doppler
probe, as previously described.50 Percent systolic
thickening fraction was calculated as the ratio of net systolic
thickening to end-diastolic wall thickness, multiplied by
100.50 As illustrated in Fig 2, the total
deficit of systolic WTh after reperfusion (an integrative
assessment of the overall severity of myocardial stunning after the
sixth reperfusion) was calculated by measuring the area between the
systolic WTh-vs-time line and the baseline (100% line) during
the 5-hour recovery phase after the sixth
reperfusion.14 15 16 45 46 51 52 In all animals, measurements
were averaged from at least 10 beats at baseline and from at least 5
beats at all subsequent time points.
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Postmortem Tissue Analysis
At the conclusion of the study, the rabbits were given heparin
(1000 U IV), after which they were anesthetized with sodium
pentobarbital (50 mg/kg IV) and euthanized with KCl. The heart was
excised, and the size of the occluded/reperfused coronary
vascular bed was determined by tying the coronary artery at the
site of the previous occlusion and by perfusing the aortic root for 2
minutes with a 0.5% solution of Monastral blue dye in normal saline at
a pressure of 70 mm Hg using a Langendorff apparatus.
The heart was then cut into 2-mm-thick transverse slices, which were
incubated for 15 minutes at 37°C in a 1% solution of
triphenyltetrazolium chloride in phosphate
buffer (pH 7.4) to verify the absence of infarction. The portion of the
LV supplied by the previously occluded coronary artery
(occluded bed) was identified by the absence of blue dye and separated
from the rest of the LV. Both components were weighed to determine the
occluded bed size as a percentage of total LV weight.
Statistical Analysis
Data are reported as mean±SEM. For intragroup comparisons,
hemodynamic variables and WTh were analyzed
by a two-way repeated-measures ANOVA (time and day) to determine
whether there was a main effect of time, a main effect of day, or a
day-by-time interaction. If the global tests showed a significant main
effect or interaction, post hoc contrasts between different time points
on the same day or between different days at the same time point were
performed with Student's t tests for paired data, and the
resulting P values were adjusted according to the Bonferroni
correction. For intergroup comparisons, continuous variables were
analyzed by either a one-way or a two-way repeated-measures
(time and group) ANOVA, as appropriate, followed by unpaired Student's
t tests with the Bonferroni correction. All statistical
analyses were performed using the SAS software
system.53 Two-way ANOVA was performed using the General
Linear Models procedure.53
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exclusions
A total of 43 conscious rabbits were used (5 for the pilot studies, 4 for the dose-response studies, and 34 for the studies of late PC). Of the 34 rabbits instrumented for the studies of late PC, 13 were assigned to the control group (group I), 14 to the L-NA–treated group (group II), and 7 to the L-NA–pretreated group (group III). Of the 13 rabbits assigned to the control group, one died of ventricular fibrillation during the fourth coronary occlusion on day 1, one could not complete day 2 because of failure of the balloon occluder, and one was excluded because of malfunction of the WTh probe. Therefore, a total of 10 control rabbits completed days 1, 2, and 3. Of the 14 rabbits assigned to the L-NA–treated group, two died of ventricular fibrillation (one during the fifth coronary occlusion on day 1 and one during the third occlusion on day 2), one could not complete day 1 because of failure of the balloon occluder, and one was excluded because of persistent dyskinesis after the sixth reperfusion on day 1 (tetrazolium staining demonstrated a myocardial infarction, probably due to malfunction of the occluder). Therefore, 10 L-NA–treated rabbits completed days 1 and 2, and 8 completed day 3. Of the 7 rabbits assigned to the L-NA–pretreated group, one was excluded because of malfunction of the WTh probe. Therefore, 6 L-NA–pretreated rabbits completed days 1, 2, and 3.
Postmortem Analysis
The size of the occluded/reperfused vascular bed was similar in
the three groups: 1.11±0.14 g (19.8±1.7% of LV weight) in group I,
1.07± 0.12 g (19.0±1.7% of LV weight) in group II, and
0.98±0.18 g (20.0±3.0% of LV weight) in group III. Tissue staining
with triphenyltetrazolium chloride
demonstrated the absence of infarction in all of the rabbits included
in the final analysis, indicating that the injury associated
with the six 4-minute occlusion/4-minute reperfusion cycles was
completely reversible.
Vasodilator Response to Acetylcholine
Studies were conducted in four rabbits to ascertain the
ability of our dose of L-NA to blunt
endothelium-dependent vasodilation. To avoid the
spontaneous fluctuations in arterial pressure that are
associated with the conscious state, the rabbits were
anesthetized with a mixture of ketamine (35 mg/kg) and
xylazine (5 mg/kg). Increasing boluses of acetylcholine were injected
intravenously before and after the administration of L-NA.
L-NA was given at the same dose and with the same protocol used in
group II. The results are illustrated in Fig 3. The
infusion of L-NA had no appreciable effect on blood pressure (mean
arterial pressure, 64.9±2.5 mm Hg before L-NA,
65.6±1.9 mm Hg 10 minutes after L-NA, and 67.3±1.7 mm Hg
30 minutes after L-NA). Before L-NA, acetylcholine decreased mean
arterial pressure by 19±2%, 32±2%, 39±1%, and 52±2%
at doses of 0.2, 0.4, 2.0, and 4.0 µg, respectively (Fig 3). Thirty
minutes after the end of L-NA infusion, the response to the same doses
of acetylcholine was markedly blunted. Even at 1 hour after L-NA was
stopped, the response to acetylcholine was still markedly suppressed
(Fig 3). The ED50 of acetylcholine was 0.33 µg before
L-NA, 2.22 µg 30 minutes after L-NA, and 3.56 µg 60 minutes after
L-NA; therefore, L-NA shifted the dose-response curve to acetylcholine
to the right by 
7-fold at 30 minutes and 11-fold at 60 minutes.
Twenty-four hours later, however, the response to acetylcholine was
back to the baseline levels (mean arterial pressure
decreased 15±1%, 27±1%, 39±1%, and 50±4% after administration
of 0.2, 0.4, 2.0, and 4.0 µg of acetylcholine, respectively). These
results demonstrate that our dose of L-NA produced partial blockade of
acetylcholine-induced vasodilation, which persisted for at least 1 hour
after treatment (interval corresponding to the sequence of six 4-minute
occlusions/4-minute reperfusion cycles in group II).
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Hemodynamic Variables
As shown in Table 1, in groups II and III the
administration of L-NA on day 1 induced a sustained decrease in heart
rate that persisted up to 4 hours after the sixth reperfusion in group
II and up to 4 hours after treatment in group III. As a result, on day
1 the heart rate was significantly lower in group II compared with
group I (control group) during the six coronary
occlusion/reperfusion cycles and for the first hour after the sixth
reperfusion (Table 1). On days 2 and 3, there were no appreciable
differences in heart rate among the three groups, either during the
sequence of coronary occlusion/reperfusion cycles or during the
5-hour reperfusion period (Table 1). A decrease in heart rate without
significant changes in arterial pressure has also been
reported by Liu et al49 after administration of the same
dose of L-NA (13 mg/kg) in conscious rabbits and by Reinhart et
al54 after administration of L-NAME in conscious dogs. In
the study by Liu et al, the effect of L-NA on heart rate was completely
blocked by atropine plus metoprolol but not by either agent alone,
indicating that it is due in part to vagal activation and in part to
sympathetic withdrawal. These results are consistent with a
central regulatory function of NO on sympathetic and parasympathetic
tone.49
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To confirm that the dose of L-NA used in the present study did not
alter systemic arterial pressure, in group II
arterial pressure was measured by cannulating the ear
dorsal artery, as detailed in "Materials and Methods." As shown
in Table 2, in group II the administration of L-NA had
no appreciable effect on mean arterial pressure on day 1
throughout the six occlusion/reperfusion cycles and the ensuing 5-hour
reperfusion interval. Furthermore, in this group, the measurements of
arterial pressure on day 2 were virtually indistinguishable
from the corresponding values on day 1 (Table 2).
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Regional Myocardial Function
Baseline systolic thickening fraction in the region to be
rendered ischemic was 37.6±1.9%, 36.0±2.2%, and 36.9±2.2%
on days 1, 2, and 3, respectively, in group I; 35.3±2.4%,
36.1±3.0%, and 31.7±1.9%, respectively, in group II; and
36.0±11.0%, 36.6±6.8%, and 33.6±7.9%, respectively, in group III.
There were no significant differences among the three groups on the
same day or among different days within the same group. In group I,
thickening fraction on day 1 was virtually identical at baseline and
after normal saline (preocclusion) (Fig 4). In group II,
thickening fraction on day 1 was 35.3±2.4% at baseline and
33.6±2.5% after administration of L-NA (preocclusion)
(P=NS, Fig 5), indicating that this agent had
no significant effect on regional myocardial function. This conclusion
is further corroborated by the results obtained on day 1 in group III,
which received L-NA without undergoing coronary occlusion. In
the three rabbits in group III in which thickening fraction was
measured on day 1, the values were 36.0±11.0% before L-NA (baseline)
and did not change appreciably after L-NA (35.1±12.0% at 1 hour,
35.6±12.8% at 2 hours, 34.3±13.0% at 3 hours, and 33.8±12.9% at 4
hours).
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indicates measurements taken on day 1; 
, measurements taken on day 3
(n=10 for all 3 days). Thickening fraction is expressed as a percentage
of Pre-O values. Data are mean±SEM.
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Figures 4, 5, and 6 demonstrate the serial measurements
of thickening fraction during the six occlusion/reperfusion cycles and
during the 5-hour recovery phase, expressed as a percentage of
preocclusion measurements, in groups I, II, and III. We shall first
describe the control group and then the L-NA–treated and –pretreated
groups.
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Group I (Control Group)
On day 1, the extent of paradoxical systolic thinning
during ischemia did not change significantly with subsequent
occlusions, so that during the sixth occlusion, it was similar to that
measured during the first occlusion (Fig 4). Similar results were
obtained on days 2 and 3. There were no significant differences among
days 1, 2, and 3 in the extent of systolic thinning during the
six occlusions.
On day 1, the thickening fraction recovered to only 34.2±6.8% of
baseline after the first coronary occlusion/reperfusion cycle
(Fig 4). Little additional deterioration was noted with the subsequent
five cycles, so that 5 minutes after the sixth reperfusion, the
thickening fraction averaged 29.8±5.9% of preocclusion values (Fig 4). Contractile function remained significantly depressed for 4 hours
after the sixth reperfusion, with the thickening fraction averaging
46.6±3.9% of preocclusion values at 30 minutes (P<.05
versus preocclusion values), 62.5±3.0% at 1 hour (P<.05),
64.4±4.3% at 2 hours (P<.05), 73.1±2.8% at 3 hours
(P<.05), and 82.3±4.2% at 4 hours (P<.05)
(Fig 4). Thus, the sequence of six 4-minute occlusions resulted in
severe myocardial stunning that lasted, on average, 4 hours.
On day 2, the recovery of WTh after the six 4-minute occlusions was
markedly improved compared with that on day 1 (Fig 4). Statistical
analysis demonstrated that the measurements of thickening
fraction were significantly greater than those on day 1 at 30 minutes
(P<.01), 1 hour (P<.05), 2 hours
(P<.01), 3 hours (P<.01), and 4 hours
(P<.01) of reperfusion. Whereas it took 5 hours for the
thickening fraction to return to 90% of baseline values on day 1,
on day 2 the thickening fraction reached 94% of baseline after just 3
hours of reperfusion. The total deficit of WTh after the sixth
reperfusion was 60% less on day 2 compared with day 1
(P<.01) (Fig 7). On day 3, the recovery of
WTh after the six 4-minute occlusions was again enhanced compared with
day 1 and similar to that observed on day 2 (Fig 4). The total deficit
of WTh after the 10th reperfusion was 55% less on day 3 compared with
day 1 (P<.01) (Fig 7). Thus, myocardial stunning was
attenuated markedly, and to a similar extent, on days 2 and 3 compared
with day 1.
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Group II (L-NA–Treated Group)
As in the control group, in group II the extent of
systolic thinning during coronary occlusion was similar
on days 1, 2, and 3 (Fig 5). Systolic thinning during occlusion
was also similar between groups I and II (Fig 5).
On day 1, the thickening fraction averaged 41.7±9.2% of preocclusion
values at 5 minutes after the sixth reflow (Fig 5). Over the ensuing 5
hours, both the recovery of WTh (Fig 5) and the total deficit of WTh
(Fig 7) were similar to those observed in the control group, indicating
that L-NA had no appreciable effect on the severity of myocardial
stunning on day 1.
On day 2, however, the results were quite different from those obtained
in the control group. Unlike the pattern observed in control rabbits,
in L-NA–treated rabbits the recovery of WTh during the 5-hour final
reperfusion period was not improved compared with day 1 (Fig 5), so
that the total deficit of WTh on day 2 was not significantly different
from that observed on day 1 (Fig 7). The total deficit of WTh on day 2
was 132% greater than the corresponding value in control rabbits
(P<.01) and was similar to that observed in control rabbits
on day 1 (Fig 7). Thus, administration of L-NA on day 1 prevented the
development of PC on day 2. On day 3, however, the recovery of WTh in
L-NA–treated rabbits was markedly improved compared with that on day 2
(Fig 5) and was similar to that noted on day 2 in the control group
(Fig 4). The total deficit of WTh was 66% less than that noted on day
2 in the same animals (P<.01) and was comparable to that
noted on day 2 in control rabbits (Fig 7). Thus, in L-NA–treated
rabbits the sequence of six coronary occlusions and
reperfusions performed on day 1 failed to precondition against stunning
on day 2, but the same sequence performed on day 2 did precondition
against stunning on day 3.
Group III (L-NA–Pretreated Group)
This group was studied to rule out the possibility that the
prevention of late PC against stunning observed on day 2 in group II
may have been caused by a delayed adverse effect on myocardial
contractility occurring as a result of L-NA
administration on day 1. On day 1, rabbits received L-NA in the absence
of ischemia and then were subjected to the coronary
occlusion/reperfusion sequence on days 2 and 3. On day 2, the recovery
of WTh during the 5 hours of reperfusion was similar to that observed
on day 1 in the control group (Fig 6), so that the total deficit of WTh
after the sixth reperfusion did not differ significantly from that
observed in control rabbits on day 1 (Fig 7). On day 3, the recovery of
WTh was significantly faster than on day 2 (Fig 6), and the total
deficit of WTh was comparable to that observed on day 2 in control
rabbits (Fig 7). Thus, administration of L-NA did not exacerbate the
severity of myocardial stunning resulting from a sequence of six
4-minute occlusion/4-minute reperfusion cycles performed 24 hours
later. These results indicate that the absence of late PC against
stunning on day 2 in group II cannot be ascribed to a delayed
deleterious action of L-NA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present investigation demonstrates that the NOS inhibitor L-NA completely blocks the development of late PC against myocardial stunning in conscious rabbits, indicating that NO generated as a result of the PC ischemia triggers the development of the cardioprotective effects observed 24 hours later. To our knowledge, this is the first study to implicate NO as a trigger of the late phase of ischemic PC. This is also the first study to examine the role of NO in ischemic PC in a conscious animal model.
The role of NO in myocardial ischemia and reperfusion appears to be more complex than that which could be inferred from its short-term effects. Previous studies have documented that NO exerts a variety of biological actions resulting in rapid but transient physiological responses.22 23 The present results expand our understanding of the role of NO in the cardiovascular system by demonstrating that this radical can serve as an intracellular signal that induces delayed long-lasting myocardial adaptations, which persist well after the enhanced generation of NO has subsided.
Methodological Considerations
The rabbit model used in this study is characterized by stable
baseline systolic WTh for several weeks after surgical
instrumentation, reproducible degrees of myocardial stunning, and
consistent development of late PC against
stunning.13 18 19 20 The rationale for using a conscious
preparation was to avoid a number of factors that could interfere with
the assessment of postischemic myocardial dysfunction, such
as anesthesia, surgical trauma, fluctuations in body
temperature, abnormal hemodynamic conditions, elevated
catecholamine levels, and cytokine
release.46 47 55 In this regard, it has been shown that
generation of ROS after brief ischemia/reperfusion is greatly
exaggerated in open-chest compared with conscious animal
preparations.45 If this difference also applies to NO,
results obtained in open-chest models may not necessarily be applicable
to the conscious state. In addition, the severity of myocardial
stunning is approximately double in open-chest compared with conscious
animal preparations.45 46 Because the primary end point of
the present study was the assessment of myocardial stunning, we
felt it was important to avoid artifactual increases in the severity of
postischemic dysfunction resulting from the open-chest
state.
The dose of L-NA was selected in pilot studies to avoid systemic
vasoconstriction, so that the effect of NOS inhibition could be
examined without the confounding influence of arterial
hypertension. Our dose of L-NA (13 mg/kg) blunted acetylcholine-induced
vasodilation for at least 1 hour (Fig 3) but did not raise
arterial pressure (Table 2), suggesting that it was
sufficient to block increased synthesis of NO (such as that which
occurs in response to ischemia/reperfusion) without decreasing
basal endothelial NO release.
Previous Studies of the Role of NO in Myocardial Stunning
Only one previous investigation has examined the effect of NOS
inhibition on myocardial stunning in vivo. In that study, Hasebe et
al56 reported that intracoronary infusion of L-NA
augmented the severity of myocardial stunning in conscious dogs
subjected to 10 minutes of coronary artery occlusion followed
by reperfusion, suggesting that NO plays an important role in
protecting the heart against postischemic dysfunction.
Regional myocardial blood flow (measured with radioactive
microspheres) decreased slightly but significantly with L-NA
infusion both before occlusion (-8.3±1.7%) and 30 minutes after
reperfusion (-7.0±1.4%).56 Because the changes in blood
flow were minimal, Hasebe et al concluded that the detrimental effect
of L-NA on myocardial stunning was unrelated to changes in regional
myocardial perfusion. In view of the differences in species,
experimental preparations, and experimental protocols, it is difficult
to compare our present results with those of Hasebe et al.
Furthermore, since heart rate was not controlled, our present
results do not enable us to determine whether L-NA affected myocardial
stunning on day 1. Although we found that the severity of myocardial
stunning on day 1 was similar in control and L-NA–treated rabbits
(group II) (Fig 5), it is still possible that a detrimental effect
would have become manifest on day 1 if heart rate had remained
constant, since the decrease in heart rate could have lessened the
severity of myocardial stunning and therefore may have offset a
detrimental effect of NOS inhibition on the recovery of WTh.
Previous Studies of the Role of NO in PC
The evidence regarding the role of NO as a possible mediator of
the early phase of ischemic PC is conflicting. Although some
studies have suggested that NO production may mediate early PC
against arrhythmias57 58 59 60 and
infarction,61 others62 63 64 65 66 have failed to
support this concept. With regard to the late phase ("second
window") of ischemic PC, no previous study has examined the
role of NO as a possible trigger. A recent investigation67
using rapid ventricular pacing (rather than
ischemia) as the PC stimulus has suggested that bradykinin may
be involved in the development of a late phase of protection against
ischemia-induced arrhythmias. However, the role of NO
as a trigger of the delayed PC effects of rapid pacing was not examined
in that study. Furthermore, it is unknown whether similar delayed
antiarrhythmic effects can be observed when brief coronary
occlusions (rather than pacing) are used as the PC stimulus.
Mechanism of Late PC Against Stunning
The mechanism(s) underlying late PC against myocardial stunning
remains largely unknown. A previous study in conscious
pigs15 provided evidence that ROS generated during the PC
ischemia on day 1 are responsible for inducing the
cardioprotective effect observed 24 hours later, but the nature of the
ROS involved was not examined. The present study provides
significant new insights by identifying NO as a major trigger of this
phenomenon. In group II, when increased synthesis of NO was blocked by
L-NA on day 1, the development of late PC on day 2 was virtually
abolished; in contrast, when NO synthesis was not blocked (day 2), a
marked PC effect became apparent 24 hours later (day 3), an effect
similar to that observed in control rabbits on day 2 (Figs 5 and 7). As
detailed in "Results," this pattern cannot be ascribed to a
delayed adverse effect of L-NA itself on the postischemic
recovery of contractile function on day 2 (independent of PC) for two
reasons: (1) the actions of L-NA on acetylcholine-induced vasodilation
and heart rate were no longer present 24 hours after its
administration, and (2) pretreatment with L-NA in group III had no
detrimental effect on the severity of myocardial stunning 24 hours
later (Fig 6). Furthermore, the failure of L-NA–treated rabbits (group
II) to develop PC on day 2 was not due to an inherent inability of the
myocardium to become preconditioned, because a marked
protective effect was observed in these animals on day 3 (Fig 5). On
the basis of these observations, we conclude that enhanced generation
of NO during the six occlusion/reperfusion cycles on day 1 is necessary
for late PC against stunning to occur; that is, increased formation of
NO represents an obligatory step in the development of the
protective response.
What is the source of increased NO generation during the PC ischemia? A likely possibility appears to be the constitutively expressed endothelial NOS, which could be stimulated by the increased shear stress associated with multiple reactive hyperemias during the six occlusion/reperfusion cycles and/or by the release of bradykinin during ischemia with subsequent activation of B2 receptors.23 A constitutive NOS has also been identified in cardiac myocytes68 69 ; increased synthesis of NO by this enzyme could occur during the PC protocol, since ischemia increases intracellular calcium levels and augments the availability of NADPH, whereas reperfusion provides the oxygen needed for NO generation.24 25
Further investigation will be necessary to elucidate the
mechanism whereby increased generation of NO during the PC
ischemia leads to the development of late PC against stunning.
By reacting with O2-, NO may form
ONOO-, OH, and other secondary reactive
species,21 25 thereby resulting in increased oxidative
stress that could, among other things, induce cardioprotective
proteins. The fact that late PC requires >6 hours to become apparent,
peaks at 24 to 72 hours, and disappears by 6 days16
suggests that it is caused by the synthesis of new proteins. Because
exposure to oxidative stress can induce both heat stress proteins and
antioxidant enzymes,70 these two groups of proteins have
been proposed as the mediators of the late phase of PC. However,
whether the induction of stress proteins plays a causative role in late
PC or is simply an epiphenomenon remains unclear.71 A role
of antioxidant enzymes seems unlikely, since late PC against stunning
is not associated with any appreciable increase in copper-zinc
superoxide dismutase, manganese superoxide dismutase, catalase,
glutathione peroxidase, or glutathione reductase.72
Besides stress proteins and antioxidant enzymes, however, it is
possible that other proteins may be induced by the PC ischemia,
since a large number of genes that are regulated by ROS have been
identified.73 74
Regarding the cardioprotective proteins potentially involved in late PC, Kim et al75 have recently shown in conscious dogs that a 10-minute coronary occlusion induces a delayed increase in the coronary flow response to endothelium-dependent vasodilators, as well as an increase in the cardiac production of NO, indicating upregulation of coronary endothelial NOS. The enhanced NO production began at 6 hours after ischemia, peaked at 24 to 48 hours, and subsided by 5 days. These observations are compatible with a role of NO (and NOS) in mediating the protective effects of the late phase of ischemic PC.75
Regardless of the nature of the proteins induced in late PC, our
working hypothesis is that enhanced synthesis of NO during the PC
stimulus may lead to upregulation of selected genes, resulting in
formation of cardioprotective proteins, which then render the heart
resistant to subsequent ischemic insults. NO could
activate gene transcription through the formation of
ONOO- and/or secondary ROS, which in turn could act via
activation of protein kinase C76 77 or via a
cis-acting regulatory element (antioxidant responsive
element) that enables cells to sense and respond to oxidative
stress.78 In addition, NO is known to bind to, and alter
the function of, several transcriptional regulatory factors, a large
number of enzymes, and various cellular proteins involved in signal
transduction, including receptors, G proteins, protein kinases, protein
phosphatases, and ion channels (reviewed in References 22 and 7922 79 ). For
example, NO has been reported to elicit nuclear translocation of
nuclear factor-
B,80 induce expression of the
c-fos and junB subunits of activator
protein 1 (AP-1),81 82 activate the cAMP-response
element binding protein (CREB),83 and elicit transcription
of phorbol ester response element (TRE)–regulated
genes.82 Since inhibition of protein kinase C abolishes
late PC against stunning,18 it seems likely that the
signaling pathway triggered by NO is mediated by this enzyme. NO may
cause protein kinase C activation not only via formation of secondary
reactive species but also through cGMP-mediated signaling. In this
regard, Maulik et al84 have suggested that by increasing
cGMP levels, NO may modulate the ischemia/reperfusion-mediated
phosphoinositide response, resulting in enhanced
generation of diacylglycerol, a general activator of
protein kinase C. These authors have also provided evidence that CO
generated by heme oxygenase contributes to the increase in
cGMP that follows NO generation, raising the possibility that CO may
play a role in ischemic PC.84
Another issue that remains to be resolved is whether the molecule that
actually triggers the development of late PC is NO itself or a
secondary reactive species derived from it. NO is known to react with
O2- at or near diffusion-limited rates,
resulting in the formation of ONOO-,25 28 a
highly reactive species that can decompose to yield OH or some
oxidant with similar reactivity.25 28 Recent studies have
documented formation of ONOO- during myocardial
ischemia/reperfusion.27 33 Thus, it is conceivable
that the signaling cascade of late PC may be initiated by
ONOO- or its byproducts. If the actual trigger of late
PC is ONOO-, then the protection should be blocked by
scavenging O2-; if the actual trigger is
ONOO--derived OH (or another similar oxidant), then the
protection should be blocked by scavenging either the precursor
(O2-) or the byproduct (OH or
similar oxidant). All of these scenarios would explain our previous
finding that late PC against stunning is abolished by the
simultaneous administration of three antioxidants targeted
at O2-, H2O2, and
OH (superoxide dismutase, catalase, and mercaptopropionyl glycine,
respectively15 ). An alternative interpretation of our
previous15 and present results, however, is that late
PC against stunning is a multifactorial phenomenon. According to this
hypothesis, ROS and NO could act via separate signaling pathways to
trigger PC, but both would be necessary to reach the threshold for the
development of protection. Eliminating either ROS or NO would result in
insufficient activation of the mechanism(s) responsible for late PC and
thus in loss of protection.
Conclusions
Our understanding of the complex functions of NO continues to
evolve. The present study expands the existing body of knowledge by
demonstrating that inhibition of NOS prevents the development of late
PC against myocardial stunning in conscious rabbits. These observations
suggest that in addition to its numerous other actions, NO plays a key
role in the delayed myocardial adaptation to brief ischemic
stresses, acting as a signaling step in the transduction pathway that
leads to increased resistance to ischemic injury. Brief bursts
of enhanced NO production would thus have long-lasting
beneficial effects on the heart. Because the late phase of PC is likely
due to upregulation of cardioprotective genes, the present results
support a new pathophysiological paradigm in which
NO acts as a modulator of cardiac gene expression in response to
ischemia and possibly other stresses. This novel, previously
unrecognized function of NO could have implications not only for
ischemic PC but also for a number of other situations that are
associated with enhanced NOS activity.
|
Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Institutes of Health grants R01 HL-43151 and HL-55757 (Dr Bolli); by American Heart Association, Kentucky Affiliate, Inc, grants KY-96-GB-32 (Dr Qiu) and KY-96-GB-31 (Dr Tang); and by the Medical Research Grant Program of the Jewish Hospital Foundation, Louisville, Ky. We gratefully acknowledge Christiane Trauss and Wen-Jian Wu for expert technical assistance and Trudy Keith and Ann Keckler for expert secretarial assistance.
Received December 6, 1996; accepted April 4, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136.
2. Jennings RB, Murry CE, Reimer KA. Preconditioning myocardium with ischemia. Cardiovasc Drugs Ther. 1991;5:933-938.[Medline] [Order article via Infotrieve]
3. Downey JM. Ischemic preconditioning: nature's own cardioprotective intervention. Trends Cardiovasc Med. 1992;2:170-176.
4. Cohen MV, Downey JM. Preconditioning during ischemia. Cardiol Rev. 1995;3:137-149.
5. Van Winkle DM, Thornton JD, Downey DM. The natural history of preconditioning: cardioprotection depends on duration of transient ischemia and time to subsequent ischemia. Coron Artery Dis. 1991;1;2:613-619.
6.
Murry CE, Richard VJ, Jennings RB, Reimer KA.
Myocardial protection is lost before contractile function recovers from
ischemic preconditioning. Am J Physiol. 1991;260:H796-H804.
7.
Cohen MV, Yang X-M, Downey JM. Conscious
rabbits become tolerant to multiple episodes of ischemic
preconditioning. Circ Res. 1994;74:998-1004.
8. Burckhartt B, Yang X-M, Tsuchida A, Mullane KM, Downey JM, Cohen MV. Acadesine extends the window of protection afforded by ischemic preconditioning in conscious rabbits. Cardiovasc Res. 1995;29:653-657.[Medline] [Order article via Infotrieve]
9.
Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori
M, Kamada T, Tada M. Delayed effects of sublethal
ischemia on the acquisition of tolerance to
ischemia. Circ Res. 1993;72:1293-1299.
10.
Marber MS, Latchman DS, Walker JM, Yellon DM.
Cardiac stress protein elevation 24 hours after brief ischemia
or heat stress is associated with resistance to myocardial
infarction. Circulation. 1993;88:1264-1272.
11.
Baxter GF, Marber MS, Patel VC, Yellon DM.
Adenosine receptor involvement in a delayed phase of myocardial
protection 24 hours after ischemic preconditioning.
Circulation. 1994;90:2993-3000.
12. Yang X-M, Baxter GF, Yellon DM, Fletcher JR, Downey JM, Cohen MV. Second window of protection in conscious rabbits. J Mol Cell Cardiol. 1994;27:A26. Abstract.
13. Qiu Y, Maldonado C, Tang XL, Bolli R. Late preconditioning against myocardial stunning in conscious rabbits. Circulation. 1995;92(suppl I):I-715. Abstract.
14. Sun J-Z, Tang X-L, Knowlton AA, Park SW, Qiu Y, Bolli R. Late preconditioning against myocardial stunning: an endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs. J Clin Invest. 1995;95:388-403.
15. Sun J-Z, Tang X-L, Park SW, Qiu Y, Turrens JF, Bolli R. Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs. J Clin Invest. 1996;97:562-576.[Medline] [Order article via Infotrieve]
16.
Tang X-L, Qiu Y, Park S-W, Sun J-Z, Kalya A, Bolli
R. Time-course of late preconditioning against myocardial
stunning in conscious pigs. Circ Res. 1996;79:424-434.
17. Ping P, Zhang J, Qiu Y, Tang X-L, Manchikalapudi S, Bolli R. Repetitive episodes of myocardial ischemia and reperfusion induce translocation of protein kinase C epsilon isoform in conscious rabbits, which is associated with late preconditioning against myocardial stunning. Circulation. 1996;94(suppl I):I-660. Abstract.
18. Qiu Y, Tang X-L, Rizvi A, Manchikalapudi S, Maldonado C, Teschner S, Bolli R. Protein kinase C mediates late preconditioning against myocardial stunning in conscious rabbits. Circulation. 1996;94(suppl I):I-184. Abstract.
19. Teschner S, Qiu Y, Tang X-L, Maldonado C, Rizvi A, Manchikalapudi S, Bagri H, Jadoon A, Bolli R. Late preconditioning against myocardial stunning in conscious rabbits: a dose-related or an all-or-none phenomenon? Circulation. 1996;94(suppl I):I-423. Abstract.
20. Maldonado C, Qiu Y, Tang X-L, Cohen MV, Auchampach J, Bolli R. Role of adenosine receptors in late preconditioning against myocardial stunning in conscious rabbits. Am J Physiol. In press.
21. Darley-Usmar V, Wiseman H, Halliwell B. Nitric oxide and oxygen radicals: a question of balance. FEBS Lett. 1995;369:131-135.[Medline] [Order article via Infotrieve]
22. Gross SS, Wolin MS. Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol. 1995;57:737-769.[Medline] [Order article via Infotrieve]
23.
Moncada S, Higgs A. The L-arginine-nitric oxide
pathway. N Engl J Med. 1993;329:2002-2012.
24. Halliwell B. Superoxide, iron, vascular endothelium and reperfusion injury. Free Radic Res Commun. 1989;5:315-318.[Medline] [Order article via Infotrieve]
25.
Beckman JS, Beckman TW, Chen J, Marshall PA.
Apparent hydroxyl radical production by peroxynitrite:
implications for endothelial injury from nitric oxide
and superoxide. Proc Natl Acad Sci U S A. 1990;87:1620-1624.
26.
Zweier JL, Broderick R, Kuppusamy P, Thompson-Gorman S,
Lutty GA. Determination of the mechanism of free radical
generation in human aortic endothelial cells exposed to
anoxia and reoxygenation. J Biol
Chem. 1994;269:24156-24162.
27.
Wang P, Zweier JL. Measurement of nitric oxide
and peroxynitrite generation in the postischemic heart:
evidence for peroxynitrite-mediated reperfusion injury.
J Biol Chem. 1996;271:29223-29230.
28. Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol. 1992;5:834-842.[Medline] [Order article via Infotrieve]
29. Morita K, Ihnken K, Buckberg GD, Sherman MP, Young HH, Ignarro LJ. Role of controlled cardiac reoxygenation in reducing nitric oxide production and cardiac oxidant damage in cyanotic infantile hearts. J Clin Invest. 1994;93:2658-2666.
30. Depré C, Hue L. Cyclic GMP in the perfused rat heart: effect of ischemia, anoxia and nitric oxide synthase inhibitor. FEBS Lett. 1994;345:241-245.[Medline] [Order article via Infotrieve]
31.
Zweier JL, Wang P, Kuppusamy P. Direct
measurement of nitric oxide generation in the ischemic heart
using electron paramagnetic resonance spectroscopy.
J Biol Chem. 1995;270:304-307.
32. Node K, Kitakaze M, Kosaka H, Komamura K, Minamino T, Tada M, Inoue M, Hori M, Kamada T. Plasma nitric oxide end products are increased in the ischemic canine heart. Biochem Biophys Res Commun. 1995;211:370-374.[Medline] [Order article via Infotrieve]
33.
Yasmin W, Strynadka KD, Schulz R. Generation of
peroxynitrite contributes to ischemia-reperfusion injury in
isolated rat hearts. Cardiovasc Res. 1997;33:422-432.
34. Hattler BG, Gorcsan J, Shah N, Oddis CV, Billiar TR, Simmons RL, Finkel MS. A potential role for nitric oxide in myocardial stunning. J Card Surg. 1994;9:425-429.[Medline] [Order article via Infotrieve]
35. Kumura E, Kosaka H, Shiga T, Yoshimine T, Hayakawa T. Elevation of plasma nitric oxide end products during focal cerebral ischemia and reperfusion in the rat. J Cereb Blood Flow Metab. 1994;14:487-491.[Medline] [Order article via Infotrieve]
36.
Ischiropoulos H, Al-Mehdi AB, Fisher AB.
Reactive species in ischemic rat lung injury: contribution of
peroxynitrite. Am J Physiol. 1995;269:L158-L164.
37. Zhang Z-G, Chopp M, Bailey F, Malinski T. Nitric oxide changes in the rat brain after transient middle cerebral artery occlusion. J Neurol Sci. 1995;128:22-27.[Medline] [Order article via Infotrieve]
38.
Moore PK, Al-Swayeh OA, Chong NWS, Evans RA, Gibson
A. N-Nitro arginine (L-NARG), a novel,
L-arginine-reversible inhibitor of
endothelium-dependent vasodilation in
vitro. Br J Pharmacol. 1990;176:219-223.
39. Chu A, Chambers DE, Lin CC, Kuehl WD, Palmer RMJ, Moncada S, Cobb FR. Effects of inhibition of nitric oxide formation on basal vasomotion and endothelium-dependent responses of the coronary arteries in awake dogs. J Clin Invest. 1991;87:1964-1968.
40.
Fineman JR, Heymann MA, Soifer SJ.
N-Nitro-L-arginine attenuates
endothelium-dependent pulmonary vasodilation in
lambs. Am J Physiol. 1991;260:H1299-H1306.
41.
Bellan JA, Minkes RK, McNamara DB, Kadowitz PJ.
N-Nitro-L-arginine selectively inhibits
vasodilator responses to acetylcholine and bradykinin in cats.
Am J Physiol. 1991;260:H1025-H1029.
42.
Ishii K, Chang B, Kerwin JF, Huang ZJ, Murad F.
N-Nitro-L-arginine: a potent
inhibitor of endothelium-derived relaxing
factor formation. Eur J Pharmacol. 1990;176:219-223.[Medline]
[Order article via Infotrieve]
43. Southan GJ, Szabo C. Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol. 1996;51:383-394.[Medline] [Order article via Infotrieve]
44.
Buxton ILO, Cheek DJ, Eckman D, Westfall DP, Sanders
KM, Keef KD.
NG-Nitro-L-arginine methyl ester and
other alkyl esters of arginine are muscarinic receptor
antagonists. Circ Res. 1993;72:387-395.
45. Li X-Y, McCay PB, Zughaib M, Jeroudi MO, Triana JF, Bolli R. Demonstration of free radical generation in the `stunned' myocardium in the conscious dog and identification of major differences between conscious and open-chest dogs. J Clin Invest. 1993;92:1025-1041.
46.
Triana JF, Li X-Y, Jamaluddin U, Thornby JI, Bolli
R. Postischemic myocardial `stunning':
identification of major differences between the open-chest and the
conscious dog and evaluation of the oxygen radical hypothesis in the
conscious dog. Circ Res. 1991;69:731-747.
47. Bolli R. Common methodological problems and artifacts associated with studies of myocardial stunning in vivo. Basic Res Cardiol. 1995;90:257-262.[Medline] [Order article via Infotrieve]
48.
Traystman RJ, Moore LE, Helfaer MA, Davis S, Banasiak
K, Williams M, Hurn PD. Nitro-L-arginine analogues: dose- and
time-related nitric oxide synthase inhibition in brain.
Stroke. 1995;26:864-869.
49. Liu J-L, Murakami H, Zucker IH. Effects of NO on baroreflex control of heart rate and renal nerve activity in conscious rabbits. Am J Physiol. 1996;39:R1361-R1370.
50.
Bolli R, Zhu WX, Thornby JI, O'Neill PG, Roberts
R. Time-course and determinants of recovery of function after
reversible ischemia in conscious dogs. Am J
Physiol. 1988;254:H102-H114.
51.
Sekili S, McCay PB, Li X-Y, Zughaib M, Sun J-Z, Tang
X-L, Thornby JI, Bolli R. Direct evidence that the hydroxyl
radical plays a pathogenetic role in myocardial `stunning' in the
conscious dog and that stunning can be markedly attenuated without
subsequent adverse effects. Circ Res. 1993;73:705-723.
52. Bolli R, Zughaib M, Li X-Y, Sun J-Z, Triana JF, McCay PB. Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function: a pathophysiological basis for chronic myocardial `stunning.' J Clin Invest. 1995;96:1066-1084.
53. SAS Institute. SAS/STAT User's Guide, Release 6.03 Edition. Cary, NC: SAS Institute; 1988:675-712.
54.
Reinhart GA, Lohmeier TE, Mizelle HL. Temporal
influence of the renal nerves on renal excretory function during
chronic inhibition of nitric oxide synthesis.
Hypertension. 1997;29:199-204.
55. Vatner SF, Braunwald E. Cardiovascular control mechanisms in the conscious state. N Engl J Med. 1975;29:970-976.
56.
Hasebe N, Shen YT, Vatner SF. Inhibition of
endothelium-derived relaxing factor enhances myocardial
stunning in conscious dogs. Circulation. 1993;88:2862-2871.
57. Vegh A, Szekeres L, Parratt J. Preconditioning of the ischaemic myocardium; involvement of the L-arginine nitric oxide pathway. Br J Pharmacol. 1992;107:648-652.[Medline] [Order article via Infotrieve]
58. Vegh A, Papp JG, Szekeres, Parratt J. The local intracoronary administration of methylene blue prevents the pronounced antiarrhythmic effect of ischaemic preconditioning. Br J Pharmacol. 1992;107:910-911.[Medline] [Order article via Infotrieve]
59. Vegh A, Papp JG, Szekeres L, Parratt JR. Prevention by an inhibitor of the L-arginine-nitric oxide pathway of the antiarrhythmic effects of bradykinin in anaesthetized dogs. Br J Pharmacol. 1993;110:18-19.[Medline] [Order article via Infotrieve]
60. Vegh A, Papp JG, Parratt JR. Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B2 receptors. Br J Pharmacol. 1994;113:1167-1172.[Medline] [Order article via Infotrieve]
61. Hartman JC, Houshyar H, Leva SC, Wall TM. A role for nitric oxide in myocardial ischemic preconditioning. Circulation. 1995;92(suppl I):I-716. Abstract.
62. Lu H-R, Remeysen P, De Clerck F. Does the antiarrhythmic effect of ischemic preconditioning in rats involve the L-arginine nitric oxide pathway? J Cardiovasc Pharmacol. 1995;25:524-530.[Medline] [Order article via Infotrieve]
63.
Woolfson RG, Patel VC, Neild GH, Yellon DM.
Inhibition of nitric oxide synthesis reduces infarct size by an
adenosine-dependent mechanism. Circulation. 1995;91:1545-1551.
64.
Weselcouch EO, Baird AJ, Sleph P, Grover GJ.
Inhibition of nitric oxide synthesis does not affect ischemic
preconditioning in isolated perfused rat hearts. Am
J Physiol. 1995;268:H242-H249.
65. Bugge E, Ytrehus K. Bradykinin can protect against infarction but does not mediate ischemic preconditioning in the rat heart. Circulation. 1995;92(suppl I):I-456. Abstract.
66.
Goto M, Liu Y, Yang X-M, Ardell JL, Cohen MV, Downey
JM. Role of bradykinin in protection of ischemic
preconditioning in rabbit hearts. Circ Res. 1995;77:611-621.
67. Vegh A, Kaszala K, Papp JG, Parratt JR. Delayed myocardial protection by pacing-induced preconditioning; a possible role for bradykinin. Br J Pharmacol. 1995;116:288P. Abstract.
68.
Balligand J-L, Kobzik L, Han X, Kaye DM, Belhassen L,
O'Hara DS, Kelly RA, Smith TW, Michel T. Nitric oxide-dependent
parasympathetic signaling is due to activation of constitutive
endothelial (type III) nitric oxide synthase in cardiac
myocytes. J Biol Chem. 1995;270:14582-14586.
69. Belhassen L, Kelly RA, Smith TW, Balligand J-L. Nitric oxide synthase (NOS 3) and contractile responsiveness to adrenergic and cholinergic agonists in the heart. J Clin Invest. 1996;97:1908-1915.[Medline] [Order article via Infotrieve]
70. Yellon DM, Latchman DS. Stress proteins and myocardial protection. J Moll Cell Cardiol. 1992;24:113-124.[Medline] [Order article via Infotrieve]
71. Heads RJ, Baxter GF, Latchman DS, Yellon DM. Delayed protection in rabbit heart following ischaemic preconditioning is associated with modulation of HSP27 and superoxide dismutase at 24 hours. J Moll Cell Cardiol. 1995;27:A163. Abstract.
72. Tang XL, Qiu Y, Turrens JF, Sun JZ, Bolli R. Is late preconditioning against myocardial stunning mediated by increased endogenous antioxidant defenses? Circulation. 1996;94(suppl I):I-184. Abstract.
73. Pahl HL, Baeuerle PA. Oxygen and the control of gene expression. Bioessays. 1994;16:497-502.[Medline] [Order article via Infotrieve]
74. Das DK, Maulik N, Moraru II. Gene expression in acute myocardial stress: induction by hypoxia, ischemia, reperfusion, hyperthermia and oxidative stress. J Moll Cell Cardiol. 1995;27:181-193.[Medline] [Order article via Infotrieve]
75. Kim S-J, Ghaleh B, Kudej RK, Hintze TH, Vatner SF. Brief periods of myocardial ischemia induce delayed upregulation of coronary vascular nitric oxide in conscious dogs. Circulation. 1996;94(suppl I):I-183. Abstract.
76.
Gopalakrishna R, Anderson WB.
Ca2+- and phospholipid-independent activation of protein
kinase C by selective oxidative modification of the regulatory
domain. Proc Natl Acad Sci U S A. 1989;86:6758-6762.
77. Downey JM, Cohen MV, Ytrehus K, Liu Y. Cellular mechanisms in ischemic preconditioning: the role of adenosine and protein kinase C. In: Das DK, ed. Cellular Biochemical and Molecular Aspects of Reperfusion Injury. New York, NY: Annals of the Academy of Sciences; 1994;723:82-98.
78.
Rushmore TH, Morton MR, Pickett CB. The
antioxidant responsive element: activation by oxidative stress and
identification of the DNA consensus sequence required for functional
activity. J Biol Chem. 1991;266:11632-11639.
79.
Kelly RA, Balligand J-L, Smith TW. Nitric oxide
and cardiac function. Circ Res. 1996;79:363-380.
80. Lander HM, Sehajpal P, Levine DM, Novogrodsky A. Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds. J Immunol. 1993;150:1509-1516.[Abstract]
81. Haby C, Lisovoski F, Aunis D, Zwiller J. Stimulation of the cyclic GMP pathway by NO induces expression of the early genes c-fos and jun-B in PC-12 cells. J Neurochem. 1994;62:496-501.[Medline] [Order article via Infotrieve]
82. Pilz RB, Suhasini M, Idriss S, Meinkoth JL, Boss GR. Nitric oxide and cGMP analogs activate transcription from AP-1-responsive promoters in mammalian cells. FASEB J. 1995;9:552-558.[Abstract]
83. Peunova N, Enikolopov G. Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells. Nature. 1993;364:450-453.[Medline] [Order article via Infotrieve]
84. Maulik N, Engelman DT, Watanabe M, Engleman RM, Rousou JA, Flack JE, Deaton DW, Gorbunov NV, Elsayed NM, Kagan VE, Das DK. Nitric oxide/carbon monoxide: a molecular switch for myocardial preservation during ischemia. Circulation. 1996;94(suppl II):II-398-II-406.
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|
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 |
|
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|
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A. J. Spanier and K. H. McDonough Dexamethasone Blocks Sepsis-Induced Protection of the Heart from Ischemia Reperfusion Injury Experimental Biology and Medicine, January 1, 2000; 223(1): 82 - 87. [Abstract] [Full Text]
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 |
|
 T. Noda, S. Minatoguchi, K. Fujii, M. Hori, T. Ito, K. Kanmatsuse, M. Matsuzaki, T. Miura, H. Nonogi, M. Tada, et al. Evidence for the delayed effect in human ischemic preconditioning: Prospective multicenter study for preconditioning in acute myocardial infarction J. Am. Coll. Cardiol., December 1, 1999; 34(7): 1966 - 1974. [Abstract] [Full Text] [PDF]
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A. Rizvi, X.-L. Tang, Y. Qiu, Y.-T. Xuan, H. Takano, A. K. Jadoon, and R. Bolli Increased protein synthesis is necessary for the development of late preconditioning against myocardial stunning Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H874 - H884. [Abstract] [Full Text] [PDF]
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R. D Rakhit, R. J Edwards, and M. S Marber Nitric oxide, nitrates and ischaemic preconditioning Cardiovasc Res, August 15, 1999; 43(3): 621 - 627. [Full Text] [PDF]
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 N.-P. Wang, B. L. Bufkin, M. Nakamura, Z.-Q. Zhao, J. N. Wilcox, K. O. Hewan-Lowe, R. A. Guyton, and J. Vinten-Johansen Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis Ann. Thorac. Surg., June 1, 1999; 67(6): 1689 - 1695. [Abstract] [Full Text] [PDF]
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J. R. Kersten and D. C. Warltier Modulation of the adaptive response to myocardial ischemia by coexisting disease Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2268 - H2270. [Full Text] [PDF]
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Y.-T. Xuan, X.-L. Tang, S. Banerjee, H. Takano, R. C. X. Li, H. Han, Y. Qiu, J.-J. Li, and R. Bolli Nuclear Factor-{kappa}B Plays an Essential Role in the Late Phase of Ischemic Preconditioning in Conscious Rabbits Circ. Res., May 14, 1999; 84(9): 1095 - 1109. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, X. Cao, R. C. X. Li, D. Kong, X.-L. Tang, Y. Qiu, S. Manchikalapudi, J. A. Auchampach, R. G. Black, et al. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1468 - H1481. [Abstract] [Full Text] [PDF]
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P. Ping, H. Takano, J. Zhang, X.-L. Tang, Y. Qiu, R. C. X. Li, S. Banerjee, B. Dawn, Z. Balafonova, and R. Bolli Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits : A Signaling Mechanism for Both Nitric Oxide–Induced and Ischemia-Induced Preconditioning Circ. Res., March 19, 1999; 84(5): 587 - 604. [Abstract] [Full Text] [PDF]
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M. Kitakaze, K. Node, T. Minamino, H. Asanuma, T. Kuzuya, and M. Hori A Ca channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs J. Am. Coll. Cardiol., January 1, 1999; 33(1): 242 - 249. [Abstract] [Full Text] [PDF]
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E. C Lascano, J. A Negroni, H. F del Valle, and A. J Crottogini Left ventricular regional systolic and diastolic function in conscious sheep undergoing ischemic preconditioning Cardiovasc Res, January 1, 1999; 41(1): 77 - 86. [Abstract] [Full Text] [PDF]
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Y. Guo, W.-J. Wu, Y. Qiu, X.-L. Tang, Z. Yang, and R. Bolli Demonstration of an early and a late phase of ischemic preconditioning in mice Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1375 - H1387. [Abstract] [Full Text] [PDF]
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H. Takano, S. Manchikalapudi, X.-L. Tang, Y. Qiu, A. Rizvi, A. K. Jadoon, Q. Zhang, and R. Bolli Nitric Oxide Synthase Is the Mediator of Late Preconditioning Against Myocardial Infarction in Conscious Rabbits Circulation, August 4, 1998; 98(5): 441 - 449. [Abstract] [Full Text] [PDF]
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H. Takano, X.-L. Tang, Y. Qiu, Y. Guo, B. A. French, and R. Bolli Nitric Oxide Donors Induce Late Preconditioning Against Myocardial Stunning and Infarction in Conscious Rabbits via an Antioxidant-Sensitive Mechanism Circ. Res., July 13, 1998; 83(1): 73 - 84. [Abstract] [Full Text] [PDF]
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R. A. Kloner, R. Bolli, E. Marban, L. Reinlib, and E. Braunwald Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning : An NHLBI Workshop Circulation, May 19, 1998; 97(18): 1848 - 1867. [Full Text] [PDF]
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D. M Yellon, G. F Baxter, D. Garcia-Dorado, G. Heusch, and M. S Sumeray Ischaemic preconditioning: present position and future directions Cardiovasc Res, January 1, 1998; 37(1): 21 - 33. [Abstract] [Full Text] [PDF]
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R. Bolli, S. Manchikalapudi, X.-L. Tang, H. Takano, Y. Qiu, Y. Guo, Q. Zhang, and A. K. Jadoon The Protective Effect of Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Is Mediated by Nitric Oxide Synthase : Evidence That Nitric Oxide Acts Both as a Trigger and as a Mediator of the Late Phase of Ischemic Preconditioning Circ. Res., December 19, 1997; 81(6): 1094 - 1107. [Abstract] [Full Text]
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Y. Qiu, A. Rizvi, X.-L. Tang, S. Manchikalapudi, H. Takano, A. K. Jadoon, W.-J. Wu, and R. Bolli Nitric oxide triggers late preconditioning against myocardial infarction in conscious rabbits Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2931 - H2936. [Abstract] [Full Text] [PDF]
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X.-L. Tang, Y. Qiu, J. F. Turrens, J.-Z. Sun, and R. Bolli Late preconditioning against stunning is not mediated by increased antioxidant defenses in conscious pigs Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1651 - H1657. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, Y. Qiu, X.-L. Tang, S. Manchikalapudi, X. Cao, and R. Bolli Ischemic Preconditioning Induces Selective Translocation of Protein Kinase C Isoforms {epsilon} and {eta} in the Heart of Conscious Rabbits Without Subcellular Redistribution of Total Protein Kinase C Activity Circ. Res., September 19, 1997; 81(3): 404 - 414. [Abstract] [Full Text]
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K. M. Kurrelmeyer, L. H. Michael, G. Baumgarten, G. E. Taffet, J. J. Peschon, N. Sivasubramanian, M. L. Entman, and D. L. Mann Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction PNAS, May 9, 2000; 97(10): 5456 - 5461. [Abstract] [Full Text] [PDF]
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H. Ninomiya, H. Otani, K. Lu, T. Uchiyama, M. Kido, and H. Imamura Enhanced IPC by activation of pertussis toxin-sensitive and -insensitive G protein-coupled purinoceptors Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1933 - H1943. [Abstract] [Full Text] [PDF]
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K. Shinmura, Y.-T. Xuan, X.-L. Tang, E. Kodani, H. Han, Y. Zhu, and R. Bolli Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning Circ. Res., March 22, 2002; 90(5): 602 - 608. [Abstract] [Full Text] [PDF]
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