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From the Experimental Research Laboratory, Division of Cardiology,
University of Louisville, Louisville, Ky.
Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail rbolli{at}louisville.edu
Methods and Results—Conscious rabbits underwent a 30-minute
coronary occlusion followed by 3 days of reperfusion. In group
I (control group, n=10), infarct size (tetrazolium staining) averaged
56.8±5.3% of the risk region, which was decreased to 27.6±2.5%
(P<0.05) in rabbits preconditioned 24 hours earlier
with a sequence of six 4-minute occlusion/4-minute reperfusion cycles
(group II, n=10). When preconditioned rabbits were given the
nonselective NOS inhibitor
N
Conclusions—Taken together, these results indicate that in the
conscious rabbit, the infarct-sparing effect of the late phase of
ischemic PC is mediated by the activity of NOS and suggest that
the specific isoform primarily responsible for this cardioprotective
phenomenon is iNOS. Thus, NO appears to be a pivotal component of the
pathophysiological cascade of late PC.
In conscious rabbits, the late phase of ischemic PC protects
both against a mild, reversible ischemic insult (myocardial
stunning)8 16 and against a severe, irreversible
ischemic insult (myocardial
infarction).15 17 Recent
studies16 have suggested that the protective
effects of late PC against stunning are mediated by augmented formation
of NO, apparently via the inducible isoform of nitric oxide synthase
(iNOS). It is unknown, however, whether NOS also mediates late PC
against infarction. Data obtained in the setting of late PC against
stunning16 cannot be extrapolated to late PC
against infarction for 2 main reasons. First, myocardial stunning and
infarction are 2 very different types of injury, so that the effect of
a putative cardioprotective agent on one may not be applicable to the
other. For example, in several experimental models, the beneficial
effects of ischemic PC are apparently restricted to either
reversible or irreversible ischemic injury but do not seem to
apply to both (eg, in dogs, the early phase of PC does not protect
against the stunning induced by a 10- or 15-minute coronary
occlusion,18 20 although it is highly effective
in protecting against infarction,4 whereas in
pigs, the late phase of PC fails to protect against the infarction
induced by a 40-minute occlusion,5 although it is
highly effective in protecting against
stunning12–14). The second reason is that
studies of the role of NO in in vivo models of myocardial infarction
have yielded conflicting results, concluding that this radical has
either a salutary21 22 or a
detrimental23 24 effect on cell death. In vitro
studies have suggested that the effects of NO on
ischemia/reperfusion injury may depend on the timing of its
formation (ie, NO was suggested to be beneficial before and during
ischemia but deleterious after
reperfusion25). In the present investigation,
we found no effect of NOS inhibition on infarct size in
nonpreconditioned myocardium. Therefore, it
remains controversial whether augmented activity of NOS (such as that
which occurs during late PC) represents a protective phenomenon
in the setting of acute myocardial infarction.
In principle, there are several plausible NOS-independent pathways
whereby late PC may limit infarct size, because myocardial
ischemia triggers a complex array of cellular adaptations,
including activation of various receptors, kinases, and transcription
factors and upregulation of numerous genes.2 26
Indeed, a number of mechanisms other than NO biosynthesis (eg,
upregulation of heat stress proteins and antioxidant enzymes) have been
proposed to account for the late phase of ischemic
PC.10 11 19 In view of all of the above
considerations, one cannot assume that the mechanism uncovered for late
PC against reversible injury (stunning)16 will
necessarily apply to late PC against cell death.
Accordingly, the present study was undertaken to explore the role
of NOS as a mediator of the late phase of PC against myocardial
infarction in conscious rabbits. To investigate whether NO
(irrespective of its source) contributes to the protective effects of
late PC, we tested the effects of the nonselective NOS
inhibitor L-NA, given before sustained ischemia, on
myocardial infarct size. Having found that L-NA abrogated late PC, we
then tested the effects of the selective iNOS inhibitor AG.
In addition to measuring infarct size, we also evaluated the recovery
of myocardial function (assessed as systolic WTh) after the
lethal ischemic insult, because this is an additional index of
myocardial protection that is independent of histochemical measurements
of cell death. The study was conducted in conscious animals to
eliminate the potentially confounding influence of factors associated
with open-chest preparations, such as anesthesia, surgical
trauma, abnormal hemodynamics, elevated
catecholamine levels, fluctuations in body temperature,
exaggerated formation of reactive oxygen species, and release of
cytokines, which could, in themselves, induce
iNOS27 and could also interfere with myocardial
infarction or ischemic PC.1 3 28 29 The
results provide evidence for the first time that late PC against
infarction is mediated by the activity of NOS.
Experimental Preparation
Experimental Protocol
Rabbits were assigned to 6 groups (Figure 1
AG was given 1 hour before ischemia because, on the basis of
the slow onset of its vascular actions30 31 and
the increase in its potency with time of
preincubation,31 32 33 this agent is thought to
enter the intracellular space relatively
slowly.34 The reason for administering AG by
subcutaneous injection was that in our previous
studies,16 we found that a dose of 100 mg/kg of
this drug given intravenously caused a sustained (>2
hours) decrease in both heart rate and arterial pressure,
possibly due to inhibition of NOS in the central nervous
system35 36 by high initial circulating levels of
AG resulting from intravenous administration. Because
several investigations have successfully used the subcutaneous route to
block iNOS activity with AG,37 38 39 40 we selected
this route in an effort to achieve lower and more sustained circulating
levels of the drug. Previous hemodynamic
measurements16 have demonstrated that
subcutaneous injection of 150 mg/kg AG has no effect on heart rate or
arterial pressure in conscious rabbits.
Postmortem Tissue Analysis
Measurement of Regional Myocardial Function
Statistical Analysis
Hemodynamic Variables
As expected,8 16 17 WTh before ischemia
was not altered by either L-NA (groups III and IV) or AG (groups V and
VI): systolic thickening fraction averaged 35.0±4.1% and
34.3±3.0% before L-NA versus 35.8±4.0% and 34.0±2.8% after L-NA
in groups III and IV, respectively, and 31.1±2.1% and 33.8±2.8%
before AG versus 31.6±1.6% and 33.2±3.2% after AG in groups V and
VI, respectively.
Region at Risk and Infarct Size
Regional Myocardial Function
The present study provides new insights into this issue. The
results reported herein demonstrate that the nonselective NOS
inhibitor L-NA completely abrogates late PC against
myocardial infarction in conscious rabbits, indicating that formation
of NO is essential for this cardioprotective phenomenon to become
manifest. The present study also demonstrates that the selective
iNOS inhibitor AG is as effective as L-NA in abrogating the
late PC effect, suggesting that iNOS is the major source of the NO that
protects against infarction. The inhibition of the infarct-sparing
action of late PC by L-NA and AG is further corroborated by our
measurements of WTh in the ischemic-reperfused region (a
tetrazolium-independent index of myocardial protection). These
measurements demonstrated that the enhanced recovery of WTh after the
30-minute coronary occlusion brought about by late PC in group
II was abolished by both of the NOS inhibitors. The effects
of L-NA and AG cannot be ascribed to an inherent detrimental action of
these agents on myocardial infarction because neither of them had any
discernible influence on infarct size in
nonpreconditioned myocardium (ie, in groups
IV and VI, respectively). Taken together, these results demonstrate
that the infarct-sparing effects of late PC are mediated by the
activity of NOS and specifically implicate iNOS as the primary
mediator. To the best of our knowledge, this is the first evidence that
NO generation is responsible for the protection against lethal injury
observed during the late phase of ischemic PC.
The mechanism of the late phase of ischemic PC involves 2 key
components: the molecular species that initiates this slow adaptive
response during the first ischemic challenge (trigger of late
PC) and the species that increases the resistance to infarction during
the second ischemic challenge (mediator of late PC). In
principle, these 2 species could be different. Previous observations
have shown that NO generated during the first ischemic insult
serves as a trigger for the development of late PC against myocardial
infarction.17 The present data expand our
understanding of the late phase of ischemic PC by demonstrating
that NO also serves as a mediator of the increased resistance to
infarction during the second ischemic insult. Therefore, the
present study reveals a much more complex, multifaceted role of NO
as a pivotal component of the entire
pathophysiological process underlying late PC.
The dose of L-NA used in the present study has been shown to
inhibit NOS activity by >70%,42 to markedly
decrease exhaled NO (measured by
chemiluminescence),35 and to blunt
acetylcholine-induced vasodilation in rabbits.8
The decrease in heart rate observed after L-NA in the present study
is consistent with previous
reports8 16 17 35 36 and is thought to reflect
the central regulatory function of NO on the sympathetic and
parasympathetic tone.35 The decrease in heart
rate elicited by L-NA, if anything, would be expected to decrease
infarct size, an effect opposite to that observed in group III. The
conclusion that the action of L-NA on heart rate did not contribute to
the abrogation of late PC in group III is further corroborated by the
results obtained in group IV, in which the same decrease in heart rate
after L-NA administration produced no detectable change in infarct
size.
Having found that L-NA abolished late PC against infarction, we then
tested the effect of AG to specifically interrogate the role of iNOS.
AG was selected among the iNOS inhibitors currently
available because it has the highest selectivity for this
isoform,34 43 44 with an
IC50 of 160.0 µmol/L for constitutive NOS
versus 5.4 µmol/L for iNOS.33 43 In
accordance with these pharmacological data in vitro, AG is
The enhancement in recovery of WTh after the 30-minute occlusion
effected by late PC (Figure 4
Although the influence of NO on lethal ischemic injury has been
addressed in several investigations, with conflicting
results,21 22 23 24 25 no previous study has examined the
role of NO as the possible mediator of the protective effects of the
late phase of ischemic PC against infarction. Zhao et
al40 have recently shown in open-chest rabbits
that the administration of monophosphoryl lipid A (MLA) elicits a
delayed infarct-sparing effect that becomes apparent 24 hours later;
this protection was associated with an increase in iNOS activity and
was inhibited by AG, suggesting that it is mediated by iNOS. It
appears, therefore, that the mechanism of pharmacological PC with MLA
resembles that of the late phase of ischemic PC.
Ischemic PC might induce expression of iNOS via activation of
protein kinase C,2 47 mitogen-activated
protein kinases,48 and/or nuclear factor
In conclusion, the present study supports the novel concept that
the infarct-sparing effect of the late phase of ischemic PC in
conscious rabbits is due to the activity of NOS and specifically the
iNOS isoform. Induction of iNOS after cellular stress generally has
been viewed as a deleterious process.50 61 The
apparent contradiction between this concept and the present
observations should stimulate a critical reassessment of current views
regarding the functional significance of iNOS induction in disease
states. We propose a more complex paradigm in which iNOS activity can
play both a beneficial and a detrimental role depending on the type of
injury and, perhaps, the intensity of iNOS induction.
Received November 11, 1997;
revision received February 2, 1998;
accepted February 13, 1998.
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© 1998 American Heart Association, Inc.
Basic Science Reports
Nitric Oxide Synthase Is the Mediator of Late Preconditioning Against Myocardial Infarction in Conscious Rabbits
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Despite intense
investigation, the effector of the infarct-limiting protection observed
during the late phase of ischemic preconditioning (PC) remains
unknown. The goal of this study was to test the hypothesis that late PC
against myocardial infarction is mediated by the activity of nitric
oxide synthase (NOS). 
-nitro-L-arginine (L-NA, 13
mg/kg IV [group III, n=8]) or the selective iNOS
inhibitor aminoguanidine (AG, 150 mg/kg SC [group V,
n=7]) before the 30-minute occlusion, the protective effect of late PC
was completely abrogated; that is, infarct size (59.9±4.5% and
65.8±3.3%, respectively) was similar to that measured in the control
group. Measurements of systolic wall thickening
(sonomicrometry) demonstrated that L-NA and AG also abolished the
improved recovery of myocardial function effected by late PC in group
II. When rabbits were given L-NA or AG without prior PC (group IV
[n=8] and group VI [n=6], respectively), infarct size did not
differ from that observed in controls (53.8±4.3% and 59.8±4.3%,
respectively), demonstrating that L-NA and AG do not increase the
extent of cell death in nonpreconditioned
myocardium.
Key Words: nitric oxide • ischemia • reperfusion • myocardial infarction
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
In addition to an
immediate infarct-sparing effect,1 2 3 4 5
ischemic PC elicits a late phase of protection against
myocardial infarction, which becomes apparent 24 hours after the
initial ischemic stress and persists up to 72
hours.5 6 7 8 9 10 11 12 13 14 15 16 17 Therapeutic exploitation of this
sustained cardioprotection would be conceptually appealing but is
hindered by the paucity of current knowledge regarding its
mechanism.18 19 In this regard, it is important
to distinguish the molecular species that initiates the development of
late PC (trigger or initiator of late PC) from that which confers
cardioprotection 24 to 72 hours later (mediator or effector of late
PC). The pathophysiological roles of these 2
species are completely different. Recent
studies17 indicate that NO is the trigger of late
PC against infarction. However, despite vigorous investigative
endeavors, the species that accounts for the delayed infarct-limiting
effects of ischemic PC (ie, the mediator of late PC) remains
unknown.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The conscious rabbit model of myocardial ischemia has
been described in detail previously8 16 17 and
will be briefly summarized here.
New Zealand White male rabbits (weight, 2.4±0.1 kg) were
instrumented under sterile conditions with a balloon occluder around a
major branch of the left coronary artery, a 10-MHz pulsed
Doppler ultrasonic crystal in the center of the region to be
rendered ischemic, bipolar pacing leads in the left atrial
appendage, and bipolar ECG leads on the chest wall. 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.
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. Regional myocardial function was assessed as
systolic thickening fraction by use of the pulsed Doppler
probe, as previously described.8 All rabbits were
subjected to a 30-minute coronary artery occlusion followed by
3 days of reperfusion. We verified the performance of
successful coronary occlusion by observing the development of
ST-segment elevation and changes in the QRS complex on the ECG and the
appearance of paradoxical wall thinning on the ultrasonic crystal
recordings. Diazepam was administered 20 minutes before the
onset of ischemia (4 mg/kg IV) to relieve the stress caused by
the coronary occlusion. No antiarrhythmic agents were given at
any time. 
). Group I (control group) underwent the
30-minute occlusion with no PC protocol and no drug treatment. Group II
(PC group) underwent a sequence of six 4-minute coronary
occlusions interspersed with 4-minute intervals of reperfusion 24 hours
before the 30-minute coronary occlusion. Group III (PC+L-NA
group) underwent the same protocol as group II except that the rabbits
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 30-minute coronary occlusion
(total dose, 13 mg/kg). L-NA (Sigma Chemical Co) was dissolved in
normal saline (total volume infused, 20 mL). Group IV (L-NA group)
underwent the same protocol as group III except that the rabbits were
not preconditioned. Group V (PC+AG group) underwent the same protocol
as group II except that the rabbits received a subcutaneous injection
of AG (150 mg/kg) 1 hour before the 30-minute coronary
occlusion. AG hydrochloride (Aldrich Chemical Co) was dissolved in
2 mL of water, and the pH of the solution was adjusted to 7.4 with 0.1
NaOH. In group VI (AG group), rabbits underwent the same protocol as in
group V except that they were not preconditioned. The solutions of L-NA
and AG were filtered through a 0.2-µm filter to ensure sterility.
View larger version (41K):
[in a new window]
Figure 1. Experimental protocol. Six groups of rabbits were
studied. On day 2, all groups underwent a 30-minute coronary
occlusion followed by 3 days of reperfusion. On day 2, rabbits in
groups I (n=10, control group) and II (n=10, PC group) received no
treatment. On day 1, rabbits in group II underwent a sequence of six
4-minute coronary occlusion/4-minute reperfusion cycles.
Rabbits in group III (n=8, PC+L-NA group) underwent the same protocol
as group II on day 1; on day 2, they received an
intravenous infusion of L-NA at a rate of 1.3 mg ·
kg-1 · min-1 starting 20 minutes
before and ending 10 minutes before the 30-minute coronary
occlusion (total dose, 13 mg/kg). Rabbits in group IV (n=8, L-NA group)
underwent the same protocol as group III except that they were not
preconditioned on day 1. Rabbits in group V (n=7, PC+AG group)
underwent the same protocol as group II on day 1; on day 2, they
received a subcutaneous injection of AG (150 mg/kg) 1 hour before the
30-minute coronary occlusion. Rabbits in group VI (n=6, AG
group) underwent the same protocol as group V except that they were not
preconditioned on day 1.
At the conclusion of the study, the size of the
occluded-reperfused coronary vascular bed was determined by a
previously described postmortem perfusion
technique.17 Briefly, the coronary artery
was tied at the site of the previous occlusion, and the aortic root was
perfused for 2 minutes with a 5% solution of Phthalo blue dye
(Heucotech LTD) in normal saline at a pressure of 70 mm Hg by use
of a Langendorff apparatus. The heart was then cut into 6
to 7 transverse slices, which were incubated for 10 minutes at 37°C
in 1% triphenyl tetrazolium chloride (pH 7.4). The slices were
weighed, fixed in a 10% formaldehyde solution, and photographed (Nikon
AF N6006). Transparencies were projected onto a paper screen at a
10-fold magnification, and the borders of the infarcted,
ischemic-reperfused, and nonischemic regions were
traced. The corresponding areas were measured by computerized
planimetry (Adobe Photoshop, version 4.0), and from these measurements,
infarct size was calculated as a percentage of the region at
risk.17
Regional myocardial function was assessed as systolic
thickening fraction by use of the pulsed Doppler probe, as
previously described.41 Percent systolic
thickening fraction was calculated as the ratio of net systolic
WTh to end-diastolic wall thickness, multiplied by
100.41 We calculated the total deficit of
systolic WTh over the 3-day reperfusion period (an integrative
assessment of the overall severity of contractile dysfunction during
this time interval) by measuring the area between the systolic
WTh-versus-time line and the baseline (100% line) during the 3-day
recovery phase after the 30-minute coronary
occlusion.17 In all animals, measurements were
averaged from 
10 beats at baseline and from 5 beats at all
subsequent time points.
Data are reported as mean±SEM. Heart rate and thickening
fraction were analyzed by a 2-way repeated-measures ANOVA (time
and group). Infarct sizes and risk region sizes were analyzed
with a 1-way ANOVA followed by Student's t tests for
unpaired data with the Bonferroni correction. The relationship between
infarct size and risk region size was compared among groups with an
ANCOVA, with size of the risk region used as the covariant. The
correlation between infarct size and risk region size was assessed by
linear regression analysis using the least squares method.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Exclusions
Of the 57 rabbits instrumented for this study, 13 were assigned to
the control group (group I), 12 to the PC group (group II), 8 to the
PC+L-NA group (group III), 8 to the L-NA group (group IV), 10 to the
PC+AG group (group V), and 6 to the AG group (group VI). Of the 13
rabbits assigned to the control group, 2 died of
ventricular fibrillation during coronary occlusion
and 1 was excluded because of failure of the balloon occluder. Of the
12 rabbits assigned to the PC group, 2 died of ventricular
fibrillation during the 30-minute coronary occlusion. Of the 10
rabbits assigned to the PC+AG group, 2 were excluded because of
ventricular fibrillation during the 30-minute occlusion and
1 because of failure of the balloon occluder. None of the rabbits
assigned to the PC+L-NA group, the L-NA group, or the AG group were
excluded. Therefore, a total of 10 rabbits completed the protocol in
the control group, 10 in the PC group, 8 in the PC+L-NA group, 8 in the
L-NA group, 7 in the PC+AG group, and 6 in the AG group. No
rabbit included in the final analysis was subjected to
defibrillation.
Previous studies in conscious rabbits have shown that the dose of
L-NA used in the present study does not alter systemic
arterial pressure or systolic thickening
fraction8 16 17 and that the dose of AG used does
not affect heart rate, arterial pressure, or
systolic thickening fraction.16 On the
day of the 30-minute coronary occlusion, baseline
(pretreatment) heart rate did not differ among the 6 groups
(Table). Consistent with our previous
studies,8 16 17 administration of L-NA produced a
sustained decrease in heart rate that persisted up to 5 hours after the
30-minute occlusion. As a result, heart rate was significantly
(P<0.05) lower in groups III and IV than in group I
(control group) after treatment (preocclusion) (185±7 and 199±5
versus 245±10 bpm, respectively), at 15 minutes of occlusion (182±7
and 175±3 versus 256±6 bpm), at 1 hour of reperfusion (182±4 and
192±7 versus 257±9 bpm), at 3 hours of reperfusion (183±4 and 192±9
versus 245±8 bpm), and at 5 hours of reperfusion (188±3 and 195±6
versus 249±8 bpm) (Table). The decreases in heart rate elicited by
L-NA in groups III and IV were similar (Table). Heart rate did not
differ significantly in groups II, V, and VI versus group I during the
30-minute occlusion or the ensuing 5 hours of reperfusion (Table).
View this table:
[in a new window]
Table 1. Heart Rate (bpm) During Coronary Occlusion and
Reperfusion
There were no significant differences among groups I, II, III, IV,
V, and VI with respect to LV weight (4.4±0.1, 4.3±0.2, 4.5±0.2,
4.8±0.2, 4.6±0.6, and 5.4±0.5 g, respectively) or weight of the
region at risk (0.8±0.1 g [18.5±2.3% of LV weight], 0.7±0.1 g
[15.6±1.3% of LV weight], 0.8±0.1 g [18.8±1.7% of LV weight],
1.0±0.1 g [20.1±1.9% of LV weight], 0.8±0.1 g [16.8±1.9% of LV
weight], and 1.1±0.1 g [21.8±3.1% of LV weight], respectively).
Average infarct size was 51% smaller in group II than in control
animals (group I) (27.6±2.5% versus 56.8±5.3% of the region at
risk, respectively; P<0.05 [Figure 2]), indicating a late PC effect against
myocardial infarction. In group III, however, infarct size (59.9±4.5%
of the region at risk) was significantly greater than in group II
(P<0.05) and essentially indistinguishable from controls
(Figure 2), indicating that L-NA abrogated the late PC effect against
infarction. In group IV, infarct size (53.8±4.3% of the region at
risk) did not differ significantly from that in controls (Figure 2),
indicating that administration of L-NA did not affect the extent of
cell death in nonpreconditioned myocardium.
Similar to the results obtained in group III, the infarct size in group
V (65.8±3.3% of the region at risk) was significantly greater than in
group II (P<0.05) and comparable to that measured in
controls (Figure 2), indicating that AG abrogated the late PC effect
against infarction. In group VI, infarct size (59.8±4.3% of the
region at risk) did not differ significantly from that in controls
(Figure 2), indicating that administration of AG in and of itself had
no effect on the magnitude of lethal injury in the absence of
ischemic PC. In all 6 groups, the size of the infarction was
positively and linearly related to the size of the region at risk
(r=0.86, 0.86, 0.85, 0.86, 0.95, and 0.75, respectively). As
expected, the regression line was significantly shifted to the right in
group II compared with group I (P<0.05 by ANCOVA) (Figure 3). In contrast, in groups III and V,
regression lines were indistinguishable from that in group I and
significantly (P<0.05 by ANCOVA) different from that in
group II, indicating that for any given size of the region at risk, the
resulting infarction was greater in preconditioned rabbits treated with
L-NA or AG than in untreated preconditioned rabbits (Figure 3).
(Regression equations are given in the legend to Figure 3).
View larger version (18K):
[in a new window]
Figure 2. Myocardial infarct size in groups I (control
group), II (PC group), III (PC+L-NA group), IV (L-NA group), V (PC+AG
group), and VI (AG group). Infarct size is expressed as a percentage of
the region at risk of infarction. Open circles represent
individual rabbits, whereas solid circles represent mean±SEM.
*P<0.05 versus group I (controls);
§P<0.05 versus group II (PC group).
View larger version (26K):
[in a new window]
Figure 3. Relationship between size of the region at risk
and size of myocardial infarction. Illustrated are both individual
values and regression lines obtained by linear regression
analysis for group I (control group), group II (PC group),
group III (PC+L-NA group), and group V (PC+AG group). In all groups,
infarct size was positively and linearly related to risk region size.
Linear regression equations were as follows: group I,
y=0.67x-0.06 (r=0.86);
group II, y=0.39x-0.07
(r=0.86); group III,
y=0.67x+0.06 (r=0.85);
group V, y=0.62x+0.02
(r=0.95). ANCOVA demonstrated that the slope of the
regression line for group II was significantly different from that for
groups I, III, or V (P<0.05 for each comparison),
indicating that for any given risk region size, infarct size was
smaller in group II than in other groups. These data demonstrate that
late PC reduced infarct size independently of risk region size and that
this effect was abrogated by both L-NA and AG.
Because of Doppler probe malfunction, complete measurements of
WTh for 3 days after reperfusion could be obtained in only 7 of 10
rabbits in group I, 9 of 10 rabbits in group II, 6 of 8 rabbits in
group III, and 4 of 7 rabbits in group V. On the second day of the
protocol, baseline systolic fraction averaged 38.7±4.5% in
group I, 37.7±2.5% in group II, 35.0±4.1% in group III, and
31.1±2.0% in group V (P=NS). After release of the
30-minute occlusion, control rabbits (group I) exhibited essentially no
recovery of WTh even at 3 days (Figure 4). In preconditioned rabbits (group II),
recovery of WTh was significantly (P<0.05) improved
compared with controls at 5 hours, 1 day, 2 days, and 3 days after
reperfusion (Figure 4). The total deficit of WTh over the 3-day
reperfusion period (an integrative assessment of the overall severity
of contractile dysfunction during this time
interval17) was decreased by 17% in group II
versus group I (P<0.05) (Figure 4). In groups III (L-NA
treated) and V (AG treated), recovery of WTh was indistinguishable from
that in the control group (Figure 4), indicating that both L-NA and AG
abrogated the salutary actions of late PC on recovery of myocardial
function.
View larger version (27K):
[in a new window]
Figure 4. Systolic thickening fraction in the
ischemic-reperfused region in groups I, II, III, and V.
Measurements were obtained at baseline, at 15 minutes into the
30-minute occlusion (Occl), and at 30 minutes and 1, 3, 5, 24, 48, and
72 hours after reperfusion. Thickening fraction is expressed as a
percentage of baseline values. Total deficit of WTh was calculated by
measuring the area between the systolic WTh-versus-time line
and the baseline (100% line) during the 3-day reperfusion period after
the 30-minute occlusion.17 Data are mean±SEM.
*P<0.05 versus group I (controls).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
One of the most critical, if not the most critical, unresolved
issues pertaining to the mechanism of late PC is the nature of the
cellular mediator that is responsible for conferring increased
tolerance to lethal ischemic injury 24 to 72 hours after a
brief ischemic challenge. The search for this mediator has been
intense, and many hypotheses have been formulated (reviewed in
Reference 1919 ). The implications of this issue are potentially vast,
because identification of the key cytoprotective protein(s) is critical
not only for understanding the pathophysiology of the delayed
myocardial adaptations to stress, but also for formulating therapeutic
strategies aimed at mimicking these adaptations with pharmacological
agents capable of inducing a sustained cardioprotective effect similar
to that afforded by the late phase of ischemic PC. 
40 times
less effective than
NG-monomethyl-L-arginine
in raising arterial blood pressure in
vivo.45 The fact that our dose of AG has no
effect on arterial blood pressure in conscious
rabbits16 further supports the notion that it
does not inhibit NO production by vascular eNOS. Our results
demonstrate that AG was as effective as L-NA in abrogating late PC
against infarction, suggesting that the primary isoform involved in
this cardioprotective phenomenon is iNOS. To the best of our knowledge,
these are the first data to implicate iNOS as a mediator of the late
phase of ischemic PC against infarction. However, because the
iNOS-versus-eNOS selectivity of any currently available NOS
inhibitor is only relative,34 a role
of eNOS as a possible mediator cannot be ruled out. In this regard, the
recent finding that brief ischemia induces a delayed
upregulation of coronary eNOS in conscious
dogs46 suggests that this enzyme may also
contribute to the protective effects of late PC. Definitive
identification of the specific isoforms of NOS responsible for late PC
will necessitate a molecular approach, such as the use of transgenic
and gene-targeted murine models of ischemic PC. The primary
objective of this investigation was to explore the role of NOS in
general, not to determine the specific NOS isoforms involved. The
concordant results obtained with 2 unrelated NOS inhibitors
provide cogent evidence to support the conclusion that NOS activity
plays a pivotal role in late PC against infarction. 
) was relatively modest compared with the
reduction in infarct size (Figure 2). However, we assessed WTh only for
the first 3 days of reperfusion. It is probable that the reduction in
the deficit of WTh would have been greater if we had monitored the
rabbits for a longer interval, sufficient for myocardial stunning in
the surviving tissue to resolve. The WTh data provide an
inde-pendent confirmation of the results obtained with
tetrazolium staining, because the effects of L-NA and AG on WTh
paralleled those on infarct size. 
B,49 ie, through signaling pathways analogous
to those involved in the induction of iNOS by
cytokines.50 Because these pathways can
be stimulated by reactive oxygen species,51 52 53 54 55 56 57 58 59
the proposal that iNOS mediates the late phase of ischemic PC
is compatible with evidence supporting an important role of reactive
oxygen metabolites in the development of this
phenomenon.13 60 The concept that iNOS protects
against infarction may seem paradoxical, or even counterintuitive, in
view of the well-known detrimental role of this enzyme in various
pathological conditions.50 61 However, because of
the differences in species, tissues, and perhaps most importantly, type
and severity of injury, it is difficult to compare previous studies of
iNOS in other systems50 61 with our present
findings. We suggest that the effects of NO are likely to be dose
dependent, so that although massive NO formation is toxic, less-robust
generation of NO may be protective to the ischemic
myocardium. Many actions of NO have been identified that
would be expected to be beneficial during acute myocardial
ischemia. For example, NO (or its second messenger, cGMP) has
been shown to inhibit the influx of calcium into
myocytes,62 63 to antagonize the effects of
ß-adrenergic stimulation,64 65 to decrease
myocardial
contractility,50 65 66 67 to reduce
myocardial oxygen consumption,68 69 70 71 and to open
KATP channels.72 73 74 These
actions may alleviate the calcium overload and depletion of high-energy
phosphates associated with acute myocardial ischemia, which are
2 of the major mechanisms of tissue injury in this setting.
Selected Abbreviations and Acronyms
AG
=
aminoguanidine
eNOS
=
endothelial nitric oxide synthase
iNOS
=
inducible nitric oxide synthase
L-NA
=
N
-nitro-L-arginine
LV
=
left ventricle
NOS
=
nitric oxide synthase
PC
=
preconditioning
WTh
=
wall thickening
Acknowledgments
This study was supported in part by NIH grants R01 HL-43151 and
HL-55757 (R.B.), by Kentucky American Heart Association Affiliate
grants KY-96-GB-32 (Y.Q.) and KY-96-GB-31 (X.-L.T.), and by the Medical
Research Grant Program of the Jewish Hospital Foundation, Louisville,
Ky. We gratefully acknowledge Christiane Trauss, Wen-Jian Wu, and Gregg
Shirk for expert technical assistance and Trudy Keith for expert
secretarial assistance.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Burckhartt B, Yang XM, Tsuchida A, Mullane KM,
Downey JM, Cohen MV. Acadesine extends the window of protection
afforded by ischaemic preconditioning in conscious rabbits.
Cardiovasc Res. 1995;29:653–657.[Medline]
[Order article via Infotrieve]
and 
in the heart of
conscious rabbits without subcellular redistribution of total PKC
activity. Circ Res. 1997;81:404–414.B and activation protein 1 in postischemic
myocardium. FEBS Lett. 1997;401:30–34.[Medline]
[Order article via Infotrieve]
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M. Lutz and H. Liu Inhaled sevoflurane produces better delayed myocardial protection at 48 versus 24 hours after exposure. Anesth. Analg., April 1, 2006; 102(4): 984 - 990. [Abstract] [Full Text] [PDF]
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M. Wakeno-Takahashi, H. Otani, S. Nakao, H. Imamura, and K. Shingu Isoflurane induces second window of preconditioning through upregulation of inducible nitric oxide synthase in rat heart Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2585 - H2591. [Abstract] [Full Text] [PDF]
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 P. C. Beguin, M. Joyeux-Faure, D. Godin-Ribuot, P. Levy, and C. Ribuot Acute intermittent hypoxia improves rat myocardium tolerance to ischemia J Appl Physiol, September 1, 2005; 99(3): 1064 - 1069. [Abstract] [Full Text] [PDF]
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R. D. Lasley, B. J. Keith, G. Kristo, Y. Yoshimura, and R. M. Mentzer Jr. Delayed adenosine A1 receptor preconditioning in rat myocardium is MAPK dependent but iNOS independent Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H785 - H791. [Abstract] [Full Text] [PDF]
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M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res, May 1, 2005; 66(2): 233 - 244. [Abstract] [Full Text] [PDF]
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 H. Yamasowa, S. Shimizu, T. Inoue, M. Takaoka, and Y. Matsumura Endothelial Nitric Oxide Contributes to the Renal Protective Effects of Ischemic Preconditioning J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 153 - 159. [Abstract] [Full Text] [PDF]
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 G. Li, F. Labruto, A. Sirsjo, F. Chen, J. Vaage, and G. Valen Myocardial protection by remote preconditioning: the role of nuclear factor kappa-B p105 and inducible nitric oxide synthase Eur. J. Cardiothorac. Surg., November 1, 2004; 26(5): 968 - 973. [Abstract] [Full Text] [PDF]
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X. Wang, C. Yin, L. Xi, and R. C. Kukreja Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2070 - H2077. [Abstract] [Full Text] [PDF]
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A. B. Stein, X.-L. Tang, Y. Guo, Y.-T. Xuan, B. Dawn, and R. Bolli Delayed Adaptation of the Heart to Stress: Late Preconditioning Stroke, November 1, 2004; 35(11_suppl_1): 2676 - 2679. [Abstract] [Full Text] [PDF]
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B. Dawn, Y.-T. Xuan, Y. Guo, A. Rezazadeh, A. B. Stein, G. Hunt, W.-J. Wu, W. Tan, and R. Bolli IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2 Cardiovasc Res, October 1, 2004; 64(1): 61 - 71. [Abstract] [Full Text] [PDF]
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Y. Wang, E. Kodani, J. Wang, S. X. Zhang, H. Takano, X.-L. Tang, and R. Bolli Cardioprotection During the Final Stage of the Late Phase of Ischemic Preconditioning Is Mediated by Neuronal NO Synthase in Concert With Cyclooxygenase-2 Circ. Res., July 9, 2004; 95(1): 84 - 91. [Abstract] [Full Text] [PDF]
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 M. Zaugg, M. C. Schaub, and P. Foex Myocardial injury and its prevention in the perioperative setting Br. J. Anaesth., July 1, 2004; 93(1): 21 - 33. [Abstract] [Full Text] [PDF]
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X.-L. Tang, Y.-T. Xuan, Y. Zhu, G. Shirk, and R. Bolli Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1273 - H1280. [Abstract] [Full Text] [PDF]
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Z. Xu, X. Ji, and P. G. Boysen Exogenous nitric oxide generates ROS and induces cardioprotection: involvement of PKG, mitochondrial KATP channels, and ERK Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1433 - H1440. [Abstract] [Full Text] [PDF]
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 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
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T. Rui, G. Cepinskas, Q. Feng, and P. R Kvietys Delayed preconditioning in cardiac myocytes with respect to development of a proinflammatory phenotype: role of SOD and NOS Cardiovasc Res, October 1, 2003; 59(4): 901 - 911. [Abstract] [Full Text] [PDF]
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 K. M. Park, J.-Y. Byun, C. Kramers, J. I. Kim, P. L. Huang, and J. V. Bonventre Inducible Nitric-oxide Synthase Is an Important Contributor to Prolonged Protective Effects of Ischemic Preconditioning in the Mouse Kidney J. Biol. Chem., July 11, 2003; 278(29): 27256 - 27266. [Abstract] [Full Text] [PDF]
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 M. Qing, K. Schumacher, R. Heise, M. Woltje, J. F. Vazquez-Jimenez, T. Richter, M. Arranda-Carrero, J. Hess, G.o. von Bernuth, and M.-C. Seghaye Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2266 - 2274. [Abstract] [Full Text] [PDF]
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Q. Li, Y. Guo, Y.-T. Xuan, C. J. Lowenstein, S. C. Stevenson, S. D. Prabhu, W.-J. Wu, Y. Zhu, and R. Bolli Gene Therapy With Inducible Nitric Oxide Synthase Protects Against Myocardial Infarction via a Cyclooxygenase-2-Dependent Mechanism Circ. Res., April 18, 2003; 92(7): 741 - 748. [Abstract] [Full Text] [PDF]
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X.-L. Tang, E. Kodani, H. Takano, M. Hill, K. Shinmura, T. M. Vondriska, P. Ping, and R. Bolli Protein tyrosine kinase signaling is necessary for NO donor-induced late preconditioning against myocardial stunning Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1441 - H1448. [Abstract] [Full Text] [PDF]
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C. Arnaud, D. Godin-Ribuot, S. Bottari, A. Peinnequin, M. Joyeux, P. Demenge, and C. Ribuot iNOS is a mediator of the heat stress-induced preconditioning against myocardial infarction in vivo in the rat Cardiovasc Res, April 1, 2003; 58(1): 118 - 125. [Abstract] [Full Text] [PDF]
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 R. M. Mentzer Jr., M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2003; 2(2003): 413 - 438. [Full Text]
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F. Kehl, P. S. Pagel, J. G. Krolikowski, W. Gu, W. Toller, D. C. Warltier, and J. R. Kersten Isoflurane Does Not Produce a Second Window of Preconditioning Against Myocardial Infarction In Vivo Anesth. Analg., November 1, 2002; 95(5): 1162 - 1168. [Abstract] [Full Text] [PDF]
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E. Kodani, Y.-T. Xuan, K. Shinmura, H. Takano, X.-L. Tang, and R. Bolli delta -Opioid receptor-induced late preconditioning is mediated by cyclooxygenase-2 in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1943 - H1957. [Abstract] [Full Text] [PDF]
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R. Bolli, K. Shinmura, X.-L. Tang, E. Kodani, Y.-T. Xuan, Y. Guo, and B. Dawn Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning Cardiovasc Res, August 15, 2002; 55(3): 506 - 519. [Abstract] [Full Text] [PDF]
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B. Dawn, H. Takano, X.-L. Tang, E. Kodani, S. Banerjee, A. Rezazadeh, Y. Qiu, and R. Bolli Role of Src protein tyrosine kinases in late preconditioning against myocardial infarction Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H549 - H556. [Abstract] [Full Text] [PDF]
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K. J. Kapinya, D. Lowl, C. Futterer, M. Maurer, K. F. Waschke, N. K. Isaev, and U. Dirnagl Tolerance Against Ischemic Neuronal Injury Can Be Induced by Volatile Anesthetics and Is Inducible NO Synthase Dependent Stroke, July 1, 2002; 33(7): 1889 - 1898. [Abstract] [Full Text] [PDF]
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R. Tissier, R. Souktani, P. Bruneval, J.-F. Giudicelli, A. Berdeaux, and B. Ghaleh Adenosine A1-receptor induced late preconditioning and myocardial infarction: reperfusion duration is critical Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H38 - H43. [Abstract] [Full Text] [PDF]
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T. Saito, F. Hu, L. Tayara, L. Fahas, H. Shennib, and A. Giaid Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H339 - H345. [Abstract] [Full Text] [PDF]
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E. Kodani, Y.-T. Xuan, H. Takano, K. Shinmura, X.-L. Tang, and R. Bolli Role of Cyclic Guanosine Monophosphate in Late Preconditioning in Conscious Rabbits Circulation, June 25, 2002; 105(25): 3046 - 3052. [Abstract] [Full Text] [PDF]
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 B. ZINGARELLI, P. W. HAKE, Z. YANG, M. O'CONNOR, A. DENENBERG, and H. R. WONG Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-{kappa}B and AP-1 activation and enhances myocardial damage FASEB J, March 1, 2002; 16(3): 327 - 342. [Abstract] [Full Text] [PDF]
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S.-J. Kim, Y.-K. Kim, G. Takagi, C.-H. Huang, Y.-J. Geng, and S. F. Vatner Enhanced iNOS function in myocytes one day after brief ischemic episode Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H423 - H428. [Abstract] [Full Text] [PDF]
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X.-L. Tang, H. Takano, A. Rizvi, J. F. Turrens, Y. Qiu, W.-J. Wu, Q. Zhang, and R. Bolli Oxidant species trigger late preconditioning against myocardial stunning in conscious rabbits Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H281 - H291. [Abstract] [Full Text] [PDF]
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R. A. Kloner and R. B. Jennings Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications: Part 1 Circulation, December 11, 2001; 104(24): 2981 - 2989. [Abstract] [Full Text] [PDF]
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R. M Bell and D. M Yellon The contribution of endothelial nitric oxide synthase to early ischaemic preconditioning: the lowering of the preconditioning threshold. An investigation in eNOS knockout mice Cardiovasc Res, November 1, 2001; 52(2): 274 - 280. [Abstract] [Full Text] [PDF]
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M. Hill, H. Takano, X.-L. Tang, E. Kodani, G. Shirk, and R. Bolli Nitroglycerin Induces Late Preconditioning Against Myocardial Infarction in Conscious Rabbits Despite Development of Nitrate Tolerance Circulation, August 7, 2001; 104(6): 694 - 699. [Abstract] [Full Text] [PDF]
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E. Kodani, K. Shinmura, Y.-T. Xuan, H. Takano, J. A. Auchampach, X.-L. Tang, and R. Bolli Cyclooxygenase-2 does not mediate late preconditioning induced by activation of adenosine A1 or A3 receptors Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H959 - H968. [Abstract] [Full Text] [PDF]
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 Y.-T. Xuan, Y. Guo, H. Han, Y. Zhu, and R. Bolli An essential role of the JAK-STAT pathway in ischemic preconditioning PNAS, July 31, 2001; 98(16): 9050 - 9055. [Abstract] [Full Text] [PDF]
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S. P. Jones, S. D. Trocha, and D. J. Lefer Cardioprotective actions of endogenous IL-10 are independent of iNOS Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H48 - H52. [Abstract] [Full Text] [PDF]
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H. E. von der Leyen and V. J. Dzau Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation Circulation, June 5, 2001; 103(22): 2760 - 2765. [Full Text] [PDF]
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Q. Li, R. Bolli, Y. Qiu, X.-L. Tang, Y. Guo, and B. A. French Gene Therapy With Extracellular Superoxide Dismutase Protects Conscious Rabbits Against Myocardial Infarction Circulation, April 10, 2001; 103(14): 1893 - 1898. [Abstract] [Full Text] [PDF]
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Y.-P. Wang, H. Xu, K. Mizoguchi, M. Oe, and H. Maeta Intestinal ischemia induces late preconditioning against myocardial infarction: a role for inducible nitric oxide synthase Cardiovasc Res, February 1, 2001; 49(2): 391 - 398. [Abstract] [Full Text] [PDF]
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 J. Feng, H. Li, and E. R. Rosenkranz Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways Ann. Thorac. Surg., December 1, 2000; 70(6): 2119 - 2124. [Abstract] [Full Text] [PDF]
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A. Lochner, E. Marais, S. Genade, and J. A. Moolman Nitric oxide: a trigger for classic preconditioning? Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2752 - H2765. [Abstract] [Full Text] [PDF]
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R. Bolli The Late Phase of Preconditioning Circ. Res., November 24, 2000; 87(11): 972 - 983. [Abstract] [Full Text] [PDF]
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H. Takano, X.-L. Tang, and R. Bolli Differential role of KATP channels in late preconditioning against myocardial stunning and infarction in rabbits Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2350 - H2359. [Abstract] [Full Text] [PDF]
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Y.-T. Xuan, X.-L. Tang, Y. Qiu, S. Banerjee, H. Takano, H. Han, and R. Bolli Biphasic response of cardiac NO synthase isoforms to ischemic preconditioning in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2360 - H2371. [Abstract] [Full Text] [PDF]
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H. Takano, X.-L. Tang, E. Kodani, and R. Bolli Late preconditioning enhances recovery of myocardial function after infarction in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2372 - H2381. [Abstract] [Full Text] [PDF]
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K. Shinmura, X.-L. Tang, Y. Wang, Y.-T. Xuan, S.-Q. Liu, H. Takano, A. Bhatnagar, and R. Bolli Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits PNAS, August 29, 2000; 97(18): 10197 - 10202. [Abstract] [Full Text] [PDF]
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T. G. Hampton, I. Amende, J. Fong, V. E. Laubach, J. Li, C. Metais, and M. Simons Basic FGF reduces stunning via a NOS2-dependent pathway in coronary-perfused mouse hearts Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H260 - H268. [Abstract] [Full Text] [PDF]
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I. Hamanaka, Y. Saito, T. Nishikimi, T. Magaribuchi, S. Kamitani, K. Kuwahara, M. Ishikawa, Y. Miyamoto, M. Harada, E. Ogawa, et al. Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H388 - H396. [Abstract] [Full Text] [PDF]
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K. Zacharowski, S. Frank, M. Otto, P. K. Chatterjee, S. Cuzzocrea, G. Hafner, J. Pfeilschifter, and C. Thiemermann Lipoteichoic Acid Induces Delayed Protection in the Rat Heart : A Comparison With Endotoxin Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1521 - 1528. [Abstract] [Full Text] [PDF]
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G. L. Semenza HIF-1: mediator of physiological and pathophysiological responses to hypoxia J Appl Physiol, April 1, 2000; 88(4): 1474 - 1480. [Abstract] [Full Text] [PDF]
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R. D. Rakhit, R. J. Edwards, J. W. Mockridge, A. R. Baydoun, A. W. Wyatt, G. E. Mann, and M. S. Marber Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1211 - H1217. [Abstract] [Full Text] [PDF]
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H. Fraser, S. T. Davidge, and A. S. Clanachan Activation of Ca2+-independent nitric oxide synthase by 17{beta}-estradiol in post-ischemic rat heart Cardiovasc Res, April 1, 2000; 46(1): 111 - 118. [Abstract] [Full Text] [PDF]
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Z. Yang, B. Zingarelli, and C. Szabo Crucial Role of Endogenous Interleukin-10 Production in Myocardial Ischemia/Reperfusion Injury Circulation, March 7, 2000; 101(9): 1019 - 1026. [Abstract] [Full Text] [PDF]
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F. Jung, L. A. Palmer, N. Zhou, and R. A. Johns Hypoxic Regulation of Inducible Nitric Oxide Synthase via Hypoxia Inducible Factor-1 in Cardiac Myocytes Circ. Res., February 18, 2000; 86(3): 319 - 325. [Abstract] [Full Text] [PDF]
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B. Dawn, Y.-T. Xuan, Y. Qiu, H. Takano, X.-L. Tang, P. Ping, S. Banerjee, M. Hill, and R. Bolli Bifunctional Role of Protein Tyrosine Kinases in Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Circ. Res., December 3, 1999; 85(12): 1154 - 1163. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, S. Huang, X. Cao, X.-L. Tang, R. C. X. Li, Y.-T. Zheng, Y. Qiu, A. Clerk, P. Sugden, et al. PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1771 - H1785. [Abstract] [Full Text] [PDF]
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K. Baghelai, L. J. Graham, A. S. Wechsler, and E. R. Jakoi Phenylephrine induces delayed cardioprotection against necrosis without amelioration of stunning Ann. Thorac. Surg., October 1, 1999; 68(4): 1219 - 1224. [Abstract] [Full Text] [PDF]
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Y. Guo, W. K. Jones, Y.-T. Xuan, X.-L. Tang, W. Bao, W.-J. Wu, H. Han, V. E. Laubach, P. Ping, Z. Yang, et al. The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene PNAS, September 28, 1999; 96(20): 11507 - 11512. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, Y.-T. Zheng, R. C. X. Li, B. Dawn, X.-L. Tang, H. Takano, Z. Balafanova, and R. Bolli Demonstration of Selective Protein Kinase C–Dependent Activation of Src and Lck Tyrosine Kinases During Ischemic Preconditioning in Conscious Rabbits Circ. Res., September 17, 1999; 85(6): 542 - 550. [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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C. S.R. Baker, O. Rimoldi, P. G. Camici, E. Barnes, M. R. Chacon, T. Y. Huehns, D. O. Haskard, J. M. Polak, and R. J.C. Hall Repetitive myocardial stunning in pigs is associated with the increased expression of inducible and constitutive nitric oxide synthases Cardiovasc Res, August 15, 1999; 43(3): 685 - 697. [Abstract] [Full Text] [PDF]
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K. Stambaugh, G. T. Elliott, K. A. Jacobson, and B. T. Liang Additive Effects of Late Preconditioning Produced By Monophosphoryl Lipid A and the Early Preconditioning Mediated By Adenosine Receptors and KATP Channel Circulation, June 29, 1999; 99(25): 3300 - 3307. [Abstract] [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, 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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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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T. C. Zhao, M. M. Taher, K. C. Valerie, and R. C. Kukreja p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart: Involvement of NF-{kappa}B and iNOS Circ. Res., November 9, 2001; 89(10): 915 - 922. [Abstract] [Full Text] [PDF]
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