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© 1998 American Heart Association, Inc.
Original Contributions |
Nitric Oxide Donors Induce Late Preconditioning Against Myocardial Stunning and Infarction in Conscious Rabbits via an Antioxidant-Sensitive Mechanism
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
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Abstract—The goal of this study was to test the hypothesis that the cardioprotective effects of the late phase of ischemic preconditioning (PC) can be mimicked by treatment with NO donors. In phase I (studies of myocardial stunning), conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3). In group I (controls, n=6), the total deficit of systolic wall thickening (WTh) after the sixth reperfusion was reduced by 54% on days 2 and 3 compared with day 1 (P<0.05), indicating a late PC effect against myocardial stunning. When rabbits were given the NO donors diethylenetriamine/NO (DETA/NO, 0.1 mg/kg IV, 4 times [group II, n=5]) or S-nitroso-N-acetylpenicillamine (SNAP, 2.5 µg · kg-1 · min-1 IV for 75 minutes [group III, n=5]) 24 hours before the first sequence of occlusion/reperfusion cycles, the deficit of WTh on day 1 was 60% (group II) and 54% (group III) less than that observed in controls (P<0.05 for both). In both groups II and III, there was no further improvement in the deficit of WTh on days 2 and 3 compared with day 1. The protective effect of DETA/NO was completely abrogated when this agent was given in conjunction with the ONOO- and ·OH scavenger mercaptopropionyl glycine (MPG) (group IV, n=5). In phase II (studies of myocardial infarction), conscious rabbits underwent a 30-minute coronary occlusion followed by 3 days of reperfusion. When rabbits were preconditioned 24 hours earlier with six 4-minute occlusion/4-minute reperfusion cycles, infarct size was reduced by 43% (33.2±2.7% versus 58.3±4.1% of the region at risk in controls, P<0.05), indicating a late PC effect against myocardial infarction. When rabbits were pretreated with DETA/NO (group VII, n=8) or SNAP (group IX, n=7) 24 hours before the 30-minute occlusion, infarct size was reduced by a similar degree (29.3±3.6% and 32.0±3.3% of the region at risk, respectively; P<0.05 versus controls). The degree of protection could not be increased by doubling the dose of DETA/NO (group VIII, n=5). Coadministration of MPG completely abrogated the infarct-sparing action of DETA/NO (group X, n=7). Taken together, these results demonstrate that in conscious rabbits the administration of 2 structurally unrelated NO donors induces protection 24 hours later against both reversible (stunning) and irreversible (infarction) ischemia/reperfusion injury and that the magnitude of this protection is indistinguishable from that observed during the late phase of ischemic PC. The fact that the late phase of ischemic PC can be mimicked by NO donors provides direct evidence that NO in itself is sufficient to elicit this cardioprotective mechanism. The fact that NO donor–induced late PC was abrogated by MPG indicates that the mechanism whereby NO induces this phenomenon involves the generation of oxidant species, possibly ONOO– and/or ·OH. Since a relatively brief treatment with hemodynamically inactive doses of NO donors can induce long-lasting protective effects, these agents could be useful for preconditioning the heart in patients.
Key Words: myocardial ischemia • myocardial reperfusion • diethylenetriamine/nitric oxide • S-nitroso-N-acetylpenicillamine
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies in rabbits have shown that ischemic PC induces a delayed cardioprotective effect that increases the tolerance of the heart both to myocardial stunning and to myocardial infarction1 2 3 4 5 6 7 ("late phase" of ischemic PC). It has recently been demonstrated that administration of NOS inhibitors (ie, L-arginine analogues) during the initial ischemic stimulus abrogates the late phase of ischemic PC, suggesting that the development of this cardioprotective phenomenon is triggered by the generation of NO ("NO hypothesis of late PC").3 4 The evidence provided by these studies,3 4 however, is indirect. There are 2 limitations inherent in pharmacological manipulations of NOS activity with L-arginine analogues. First, a nonspecific action of these agents cannot be excluded. Second, increasing evidence suggests that NOS may produce ·O2- rather than NO under conditions in which the local tissue levels of L-arginine or tetrahydrobiopterin drop.8 9 10 If this were the case during brief myocardial ischemia/reperfusion, the trigger for late PC could be an increased generation of ·O2- by NOS, not an increased generation of NO, and the mechanism by which L-arginine analogues prevent late PC could be the prevention of ·O2- formation rather than inhibition of NO synthesis. Assessing the role of NOS-generated ·O2- in vivo is problematic, because direct measurements of ·O2- in vivo are difficult and specific intracellular scavengers of ·O2- that can be used in vivo are not available. Both of the aforementioned issues, however, could be addressed by determining whether NO donors can reproduce the protective effects of the late phase of ischemic PC in the absence of ischemia. If so, this would provide direct evidence that NO (instead of, or in conjunction with, ·O2-) can indeed trigger late PC.
Besides these pathophysiological issues, there are
other cogent reasons for testing the hypothesis that exogenous NO
mimics the late phase of ischemic PC. Because of its sustained
nature, late PC may have considerable clinical relevance as a
cardioprotective mechanism that could be exploited therapeutically to
minimize ischemic injury in patients with coronary
artery disease.11 The identification of
pharmacological interventions that are capable of mimicking the
protective actions of late PC represents a critical step in
this direction, since it would provide a framework for developing
clinically applicable strategies aimed at maintaining a chronically
preconditioned state in individuals at risk for myocardial infarction
or other acute coronary events. Accordingly, in recent years
the search for pharmacological triggers of late PC has been intense. A
number of agents (eg, adenosine A1
receptor agonists,2 direct activators
of protein kinase C,6 11 
-adrenergic
agonists,12 endotoxin,13
cytokines,14 and monophosphoryl lipid
A15) have been shown to elicit a late PC–like
effect, but most of these compounds are impractical for clinical use,
and none has yet been found suitable for clinical application.
Therefore, the search for a clinically applicable intervention that can
reproduce the cardioprotective effects of the late phase of
ischemic PC continues.
NO donors, such as nitrates, have been widely used for the treatment of coronary artery disease for over a century. They are well tolerated and have relatively few side effects. In view of the mounting evidence suggesting that NO triggers the development of the late phase of ischemic PC,3 4 it seems logical to test whether pretreatment with NO donors, in the absence of ischemia, can reproduce the protective actions of late PC. If so, a new dimension would be added to the clinical role of NO-releasing agents.
The goals of the present study were to investigate (1) whether pretreatment with NO donors induces a delayed cardioprotective effect, (2) if so, whether such an effect is quantitatively equivalent to that induced by ischemic PC, and (3) whether it is mediated by ROS. To comprehensively analyze the spectrum of cardioprotection afforded by late PC, we tested the ability of NO donors to elicit delayed protection against both a mild reversible ischemic insult (myocardial stunning) and a severe irreversible insult (myocardial infarction). In an effort to exclude nonspecific effects of NO donors, 2 structurally unrelated agents, DETA/NO and SNAP, were tested in each experimental setting (stunning and infarction). To directly compare the effects of NO donors with those of ischemic PC, a well-characterized rabbit model was used in which a sequence of six 4-minute occlusion/4-minute reperfusion cycles elicits robust protection against both myocardial stunning3 5 6 and myocardial infarction.4 7 To examine the role of ROS as intermediary steps in the signal transduction pathway initiated by NO, we examined whether the thiol compound MPG, a scavenger of ONOO- and ·OH,16 17 blocks NO donor–induced late PC. All studies were conducted in conscious animals in order to eliminate potential artifacts associated with open-chest preparations.18 19 20 21 22
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental Preparation and Protocol
The experimental preparation has been described in detail previously.3 4 5 6 7 Briefly, New Zealand White male rabbits (weight, 2.0 to 2.5 kg; age, 3 to 4 months) 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, and bipolar ECG leads on the chest wall. The animals 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. Left ventricular systolic WTh, range gate depth, and the ECG were recorded throughout the experiments on a thermal array chart recorder (Gould TA6000). The study consisted of 2 consecutive phases (phase I and phase II).
Phase I: Studies of Myocardial Stunning
The experimental protocol consisted of 3 consecutive days of
coronary artery occlusions (days 1, 2, and 3, respectively). On
each day, the rabbits were subjected to a sequence of six 4-minute
coronary occlusion/4-minute reperfusion cycles (Figure 1
). 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. No sedative or antiarrhythmic
agents were given at any time.
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Rabbits were assigned to four groups (Figure 1
). Group I (control
group) underwent the coronary artery occlusion/reperfusion
protocol on days 1, 2, and 3 without any treatment. In group II
(DETA/NO group), rabbits received 4 consecutive intravenous
bolus doses of DETA/NO (0.1 mg/kg each) every 25 minutes (total dose,
0.4 mg/kg) 24 hours before the first sequence of coronary
occlusion/reperfusion cycles. In group III (SNAP group), rabbits
received a continuous intravenous infusion of SNAP (2.5
µg · kg-1 ·
min-1 for 75 minutes) 24 hours before the first
sequence of coronary occlusion/reperfusion cycles. As a result
of this protocol, both DETA/NO and SNAP were given over a 75-minute
interval. In group IV (DETA/NO+MPG group), rabbits received the same
dose of DETA/NO as in group II; in addition, they were given a
continuous intravenous infusion of MPG (1.7 mg ·
kg-1 · min-1)
beginning 1 hour before the first DETA/NO injection and continuing
until 3 hours after the fourth DETA/NO injection. This dose of MPG was
chosen because it has previously been shown to be effective (given
together with superoxide dismutase and catalase) in abrogating late PC
against stunning in pigs without causing any
hemodynamic changes.23 DETA/NO
(Alexis Corp) was dissolved in PBS (total volume infused, 4 mL); SNAP
(Sigma Chemical Co) was dissolved in normal saline (total volume
infused, 
11 mL). Both DETA/NO and SNAP were dissolved immediately
before the infusion; to remove oxygen from the solution, both the PBS
and the normal saline solutions were bubbled with nitrogen for at least
30 minutes before dissolving DETA/NO or SNAP. MPG (Sigma) was dissolved
in sterile water; because the pH of the solution was 1.0 to 2.0,
0.1 mmol/L NaOH was added to bring the pH to 7.5. All solutions
were filtered through a 0.2-µm Millipore filter to ensure
sterility.
Phase II: Studies of Myocardial Infarction
To examine the effect of NO donor pretreatment on myocardial
infarction, rabbits were subjected to a 30-minute coronary
artery occlusion followed by 3 days of reperfusion. Diazepam was
administered 20 minutes before the onset of ischemia (4 mg/kg
IP) to relieve the stress caused by the coronary occlusion. No
antiarrhythmic agents were given at any time. Rabbits were assigned to
6 groups (Figure 2). Group V (control
group) underwent the 30-minute occlusion with no PC protocol or drug
pretreatment. Group VI (ischemic PC group) was preconditioned
with a sequence of six 4-minute coronary occlusion/4-minute
reperfusion cycles 24 hours before the 30-minute coronary
occlusion. Group VII (DETA/NO group) was given 4 consecutive
intravenous bolus doses of DETA/NO (0.1 mg/kg) every 25
minutes (total dose, 0.4 mg/kg) 24 hours before the 30-minute
coronary occlusion (this is the same dose that was used in
group II). To determine whether higher doses of DETA/NO would be more
effective, group VIII (DETA/NO high-dose group) received 8 consecutive
intravenous bolus doses of DETA/NO every 25 minutes (total
dose, 0.8 mg/kg) 24 hours before the 30-minute coronary
occlusion. Group IX (SNAP group) received a continuous
intravenous infusion of SNAP (2.5 µg ·
kg-1 · min-1 for
75 minutes) 24 hours before the 30-minute coronary occlusion
(this is the same dose that was used in group III). In Group X
(DETA/NO+MPG group), rabbits were given the same dose of DETA/NO as in
group VII; in addition, they received a continuous infusion of MPG (1.7
mg · kg-1 ·
min-1) beginning 1 hour before the first DETA/NO
injection and continuing until 3 hours after the fourth injection (this
is the same treatment that was used in group IV).
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Measurement of Regional Myocardial Function
Regional myocardial function was assessed as systolic
thickening fraction using the pulsed Doppler probe, as previously
described.3 In the studies of myocardial
stunning, the total deficit of systolic WTh (an integrative
assessment of the overall severity of myocardial stunning) was
calculated by measuring the area between the systolic
WTh–versus–time line and the baseline (100% line) during the 5-hour
recovery phase after the sixth reperfusion.3 5 6
In the studies of myocardial infarction, the total deficit of
systolic WTh was calculated by the same method during the
72-hour recovery phase after the 30-minute
occlusion.4 7 In all animals, measurements from
at least 10 beats were averaged at baseline and from at least 5 beats
at all subsequent time points.
Measurement of Region at Risk and Infarct Size
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 ischemic/reperfused region (region
at risk) 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 5% solution of Phthalo blue dye in normal saline at a
pressure of 70 mm Hg using a Langendorff apparatus.
The heart was then cut into 6 to 7 transverse slices, which were
incubated for 10 minutes at 37°C in a 1% solution of
triphenyltetrazolium chloride in phosphate
buffer (pH 7.4). All atrial and right ventricular tissues
were excised. In the studies of myocardial stunning (phase I), the
region at risk (which was identified by the absence of blue dye) was
separated from the rest of the left ventricle, and both components were
weighed. In the studies of myocardial infarction (phase II), the slices
were weighed, fixed in a 10% neutral buffered 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.4 7
Statistical Analysis
Data are reported as mean±SEM. For intragroup comparisons,
hemodynamic variables and WTh were analyzed
by a 2-way repeated-measures ANOVA (time and day) followed by Student
t tests for paired data with the Bonferroni correction. For
intergroup comparisons, data were analyzed by either a 1-way or
a 2-way repeated-measures (time and group) ANOVA, as appropriate,
followed by unpaired Student t tests with the Bonferroni
correction. The relationship between infarct size and risk region size
was compared among groups with an ANCOVA using the size of the risk
region as the covariate.4 7 The correlation
between infarct size and risk region size was assessed by linear
regression analysis using the least squares method. All
statistical analyses were performed using the SAS software
system.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 94 rabbits were used in the present study (11 for the pilot studies, 6 for the studies of vasodilator response to DETA/NO, and 77 for the studies of late PC).
Pilot Studies
Pilot studies were conducted in 11 rabbits to identify the doses
of DETA/NO and SNAP that have no effect on heart rate,
arterial blood pressure, and systolic WTh. The
concern was that hemodynamic perturbations caused by
these agents (eg, a fall in blood pressure or an increase in heart
rate) could contribute nonspecifically to induce a late PC effect
unrelated to the direct actions of NO on the heart.
Arterial pressure was measured by cannulating the ear
dorsal artery with a 22-gauge angiocatheter under local
anesthesia (benzocaine), as previously
described.3
In 1 rabbit, a dose of 0.2 mg/kg of DETA/NO caused a sustained
(20-minute) decrease in blood pressure (-14%), which was associated
with a sustained (60-minute) increase in heart rate (12%). Therefore,
we reduced the dose to 0.1 mg/kg, which did not cause any appreciable
change in arterial pressure, heart rate, or WTh. In 4
rabbits, 2 intravenous bolus doses of 0.1 mg/kg of DETA/NO
were given 25 minutes apart 24 hours before the 6 occlusion/reperfusion
cycles; although 3 of the 4 rabbits were protected against stunning,
the fourth rabbit was not. We therefore increased the number of bolus
doses to 4, which proved to be effective in inducing protection against
stunning 24 hours later (group II). The rationale for dividing the
total dose of DETA/NO in multiple bolus doses given at 25-minute
intervals was to administer an amount of drug sufficient to elicit a
late PC effect without the hemodynamic changes that
would have been associated with a single large bolus. With regard to
SNAP, infusion rates of 
10 µg ·
kg-1 · min-1 have
been shown to induce a significant decrease in blood pressure
(-20%) and a significant increase in heart rate
(20%).24 In 3 rabbits, we infused SNAP at a
rate of 5 µg · kg-1 ·
min-1 for 75 minutes; this dose also caused a
significant increase in heart rate (15%). We therefore lowered the
infusion rate of SNAP to 2.5 µg ·
kg-1 · min-1,
which did not induce appreciable changes in heart rate,
arterial pressure, or WTh. The duration of SNAP infusion
(75 minutes) was chosen to correspond to the time interval during which
the 4 bolus doses of DETA/NO were administered in group II. In summary,
these pilot studies demonstrate that the doses of DETA/NO and SNAP
selected in this protocol are the highest that can be given to
conscious rabbits without causing hemodynamic
perturbations.
Vasodilator Response to DETA/NO
Studies were conducted in 6 rabbits to rule out the possibility
that MPG may scavenge NO. To avoid the spontaneous fluctuations in
arterial pressure that are associated with the conscious
state, the rabbits were anesthetized with sodium pentobarbital
(20 mg/kg). MPG was given at the same rate and with the same
protocol used in groups IV and X (1.7 mg ·
kg-1 · min-1 as a
continuous intravenous infusion). Increasing bolus doses of
DETA/NO were injected intravenously at 25-minute intervals
before and during the infusion of MPG. The results are illustrated in
Figure 3. The infusion of MPG had no
appreciable effect on blood pressure (mean arterial
pressure, 63±4 mm Hg before MPG and 65±3 mm Hg 60 minutes
after the beginning of the continuous infusion of MPG). Before MPG,
DETA/NO decreased mean arterial pressure dose-dependently
(-9.4±0.9%, -14.0±2.3%, -21.8±3.8%, and -26.3±3.5% at doses
of 0.25, 0.5, 1.0, and 1.5 mg/kg, respectively) (Figure 3). The first
bolus of DETA/NO (0.25 mg/kg) was given 60 minutes after the beginning
of the infusion of MPG, and the fourth bolus (1.5 mg/kg) was given 135
minutes after the beginning of the MPG infusion (the timing of the
DETA/NO bolus doses with respect to the MPG infusion was the same as
that used in groups IV and X [Figures 1 and 2, respectively]). Both
at 60 and 135 minutes into the infusion of MPG, the response to DETA/NO
was similar to that observed before MPG (Figure 3). These results
demonstrate that our dose of MPG did not affect DETA/NO-induced
vasodilatation, indicating that MPG is unlikely to scavenge NO.
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Phase I: Studies of Myocardial Stunning
Exclusions and Postmortem Analysis
Of the 21 rabbits instrumented for the studies of myocardial
stunning, 6 were assigned to group I (control group), 5 to group II
(DETA/NO group), 5 to group III (SNAP group), and 5 to group IV
(DETA/NO+MPG group). All of the animals completed the protocol
satisfactorily and were included in the data analysis.
Postmortem analysis showed that the size of the
occluded/reperfused vascular bed was similar in the 4 groups:
0.82±0.08 g (17.0±1.8% of LV weight) in group I, 0.92±0.16 g
(18.0±1.5% of LV weight) in group II, 0.96±0.12 g (18.9±2.2% of LV
weight) in group III, and 0.88±0.10 g (16.9±1.9% of LV weight) in
group IV. Tissue staining with
triphenyltetrazolium chloride confirmed the
absence of infarction in all animals. In all rabbits, the ultrasonic
crystal was found to be at least 3 mm from the boundaries of
the ischemic/reperfused region.
Hemodynamic Variables
There were no significant changes in heart rate,
arterial blood pressure, or systolic WTh at any
time during or after the administration of DETA/NO, SNAP, or
DETA/NO+MPG in groups II, III, and IV, respectively
(representative measurements are given in Table 1). These results are in agreement with
our pilot studies and confirm that the doses of NO donors selected in
this study have no effects on hemodynamic variables
or regional myocardial function in conscious rabbits. On days 1, 2, and
3, there were no appreciable differences in heart rate among the 4
groups, either during the sequence of coronary
occlusion/reperfusion cycles or during the 5-hour reperfusion period
(Table 2).
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Regional Myocardial Function
Baseline systolic thickening fraction on days 1, 2, and 3
averaged 37.4±5.5%, 35.5±4.4%, and 36.4±4.6%, respectively, in
group I; 40.8±3.5%, 41.9±3.6%, and 43.2±4.3% in group II;
38.0±2.7%, 39.1±2.7%, and 36.3±2.2% in group III; and
41.3±1.2%, 41.3±1.4%, and 41.7±1.3% in group IV. There were no
significant differences among groups I, II, III, and IV on the same
day, or among different days within the same group. Furthermore, within
the same group there were no significant differences among days 1, 2,
and 3 with respect to the extent of paradoxical systolic
thinning during the 6 occlusions (Figures 4 to 7).
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Group I (Control Group)
On day 1, the thickening fraction remained significantly
(P<0.05) depressed for 4 hours after the sixth reperfusion
and recovered by 5 hours (Figure 4), indicating that the sequence of
six 4-minute occlusion/4-minute reperfusion cycles resulted in severe
myocardial stunning that lasted, on average, 4 hours. On days 2 and 3,
however, the recovery of WTh after the 6 occlusion/reperfusion cycles
was markedly improved compared with WTh recovery on day 1 (Figure 4).
The total deficit of WTh after the sixth reperfusion was 54% less on
both days 2 and 3 compared with day 1 (P<0.01) (Figure 8).
Thus, as expected,3 5 6 myocardial stunning was
attenuated markedly, and to a similar extent, on days 2 and 3 compared
with day 1.
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Groups II (DETA/NO Group) and III (SNAP Group)
Although on day 1 the extent of paradoxical wall
thinning in groups II and III was similar to that noted in control
rabbits, the recovery of WTh after the sixth reperfusion was markedly
faster than in the control group, and this improvement was sustained
throughout the entire reperfusion interval (Figures 5 and 6). The total
deficit of WTh in groups II and III was 60% less and 54% less,
respectively, than that observed in control rabbits on day 1
(P<0.05) and similar to that observed in control rabbits on
days 2 and 3 (Figure 8). On days 2 and 3,
there was no further improvement in either the recovery of WTh (Figures 5 and 6) or the total deficit of WTh (Figure 8) compared with day 1.
Thus, administration of either DETA/NO or SNAP 24 hours before
the sequence of six 4-minute occlusion/reperfusion cycles resulted in
an attenuation of myocardial stunning on day 1 that was essentially
equivalent to that effected by ischemic PC.
Group IV (DETA/NO+MPG Group)
The combination of DETA/NO and MPG was studied to elucidate the
mechanism of the PC effect induced by DETA/NO and, specifically, to
determine whether it was mediated by the formation of MPG-sensitive
oxidants (·OH and ONOO-). On day 1, both the
recovery of WTh (Figure 7) and the total deficit of WTh (Figure 8) were
virtually indistinguishable from those noted in the control group,
indicating the absence of PC against stunning. Thus, the PC effect
induced by DETA/NO was completely abrogated by the concomitant
administration of MPG. A PC effect became apparent on days 2 and 3, as
documented by the enhanced recovery of WTh (Figure 7) and the reduced
deficit of WTh (Figure 8) compared with those values on day 1.
Phase II: Studies of Myocardial Infarction
Exclusions and Arrhythmias
Of the 56 rabbits instrumented for the studies of myocardial
infarction, 13 were assigned to group V (control group), 12 to group VI
(ischemic PC group), 9 to group VII (DETA/NO group), 6 to group
VIII (DETA/NO high-dose group), 8 to group IX (SNAP group), and 8 to
group X (DETA/NO+MPG group). Six rabbits died of
ventricular fibrillation during coronary occlusion
(2 in group V, 2 in group VI, 1 in group VIII, and 1 in group IX), and
1 died after reperfusion (in group X). Two rabbits (1 in group V and 1
in group VII) were excluded because of technical problems during the
postmortem analysis. Therefore, the total number of rabbits
that completed the experimental protocol was 10 in group V, 10 in group
VI, 8 in group VII, 5 in group VIII, 7 in group IX, and 7 in group X.
No rabbit included in the final analysis was subjected to
defibrillation.
In the control group, 15% of the rabbits (2 of 13) developed ventricular fibrillation during the 30-minute occlusion, and 36% (4 of 11) developed ventricular tachycardia after reperfusion (no control rabbit exhibited ventricular fibrillation after reperfusion). The incidence of ventricular fibrillation during the 30-minute occlusion and ventricular tachycardia after reperfusion did not differ significantly between the control and treated groups (data not shown).
Hemodynamic Variables
In agreement with our pilot studies, no significant changes in
heart rate, arterial blood pressure, or systolic
WTh were observed at any time during or after the administration of
DETA/NO, high-dose DETA/NO, SNAP, or DETA/NO+MPG in groups VII, VIII,
IX, and X, respectively (representative measurements
are given in Table 1). Furthermore, there were no appreciable
differences in heart rate among groups V, VI, VII, VIII, IX, and X
during the 30-minute coronary occlusion or during the 72-hour
reperfusion period (representative measurements are
shown in Table 2). Baseline systolic thickening fraction was
also similar among the 6 groups (38.7±4.5%, 38.8±2.9%, 35.3±4.4%,
37.4±1.6%, 38.6±5.3%, and 36.3±3.3% in groups V, VI, VII, VIII,
IX, and X, respectively).
Region at Risk and Infarct Size
There were no significant differences among groups V, VI, VII,
VIII, IX, and X with respect to the weight of the region at risk
(0.68±0.08 g [15.1±1.3% of LV weight], 0.69±0.08 g [15.5±1.7%
of LV weight], 0.68±0.07 g [15.0±1.5% of LV weight], 0.66±0.06 g
[15.3±1.5% of LV weight], 0.61±0.02 g [14.9±0.8% of LV
weight], and 0.72±0.07 g [16.0±1.4% of LV weight], respectively).
The average infarct size was 43% smaller in group VI (ischemic
PC group) compared with group V (control group) (33.2±2.7% versus
58.3±4.1% of the region at risk, respectively; P<0.05
[Figure 9]), indicating a late PC
effect against myocardial infarction. A quantitatively similar PC
effect was observed in groups VII (DETA/NO group) and IX (SNAP group):
the average infarct size in these groups (29.3±3.6% and 32.0±3.3%
of the region at risk, respectively) was similar to that measured in
group VI and significantly (P<0.05) smaller than that
measured in group V (Figure 9), indicating that pretreatment with these
NO donors 24 hours before the 30-minute occlusion resulted in a
protective effect that was equivalent to that induced by
ischemic PC in group VI. Although group VIII was given 0.8
mg/kg of DETA/NO instead of the 0.4 mg/kg given to group VII, infarct
size in these rabbits was not smaller than in group VII (Figure 9),
indicating that the protection could not be enhanced by doubling the
dose of the NO donor. In group X, infarct size was indistinguishable
from that measured in the control group and significantly
(P<0.05) larger than that measured in group VII (Figure 9), indicating that MPG completely blocked the infarct-sparing effect
of DETA/NO pretreatment.
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Since the effects of DETA/NO and SNAP on infarct size in groups VII,
VIII, and IX were indistinguishable (Figure 9), the rabbits in these 3
groups were pooled together (NO donor group) for the analysis
of the infarct–risk region relationship (Figure 10) and of the recovery of WTh (Figure 11). In all groups, the size of the
infarction was positively and linearly related to the size of the
region at risk (r=0.93 in the control group,
r=0.79 in the ischemic PC group, and
r=0.66 in NO donor–pretreated rabbits [groups VII, VIII,
and IX pooled together], and r=0.90 in the DETA/NO+MPG
group) (Figure 10). As expected,4 7 the
regression line was shifted to the right in the ischemic PC
group compared with the control group (P<0.05 by ANCOVA)
(Figure 10). In the 3 groups pretreated with NO donors, the regression
line was virtually indistinguishable from that of the ischemic
PC group and was significantly shifted to the right compared with that
of the control group (P<0.05 by ANCOVA) (Figure 10),
indicating that for any given size of the region at risk, the resulting
infarct size was reduced by pretreatment with DETA/NO or SNAP and that
the magnitude of this effect was similar to that induced by
ischemic PC. In contrast, in the DETA/NO+MPG group (group X),
the regression line did not differ from that observed in the control
group (Figure 10).
|
|
Regional Myocardial Function
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 V, 7 of 10 rabbits in group VI, 3 of 8 rabbits in
group VII, 2 of 5 rabbits in group VIII, 4 of 7 rabbits in group IX,
and 5 of 7 rabbits in group X. After release of the 30-minute
occlusion, control rabbits (group V) exhibited essentially no recovery
of WTh, even at 3 days (Figure 11). In rabbits preconditioned with
ischemia (group VI), the recovery of WTh was significantly
(P<0.05) improved compared with control rabbits at 3 hours,
5 hours, 24 hours, and 72 hours after reperfusion (Figure 11). The
total deficit of WTh during the 72 hours of reperfusion was 18% less
in group VI versus group V (P<0.05) (Figure 11). In the
rabbits pretreated with NO donors (groups VII, VIII, and IX combined,
n=9), the recovery of WTh was similar to that noted in the rabbits
preconditioned with ischemia and significantly
(P<0.05) improved compared with control rabbits at 1 hour,
3 hours, 5 hours, 24 hours, and 72 hours after reperfusion (Figure 11).
The total deficit of WTh during the 72-hour reperfusion period was 23%
less in NO donor–pretreated rabbits versus control rabbits
(P<0.05) (Figure 11). Thus, pretreatment with NO donors
resulted in enhanced recovery of myocardial contractile function, which
became evident soon after reperfusion (1 hour) and was sustained
throughout the 72-hour reperfusion interval; the magnitude of this
effect was similar to that observed after ischemic PC in group
VI. In the DETA/NO+MPG group, both the recovery of WTh and the total
deficit of WTh were similar to those observed in the control group
(Figure 11), indicating that the salutary actions of NO donor
pretreatment on the recovery of myocardial function were abrogated by
the concomitant administration of MPG. Since the effects of
ischemic PC, NO donors, and MPG on WTh paralleled those on
infarct size (Figure 9), the WTh data provide an independent
confirmation of the results obtained with tetrazolium staining.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Before the NO hypothesis of late PC can be conclusively accepted, it is necessary to verify that the effects of exogenous NO mimic those of the late phase of ischemic PC. The present study demonstrates that administration of 2 structurally different NO donors, in the absence of ischemia, induces a significant protection against myocardial ischemia/reperfusion injury 24 hours later, which is indistinguishable from that observed during the late phase of ischemic PC. This NO-induced late PC was effective in reducing not only the severity of myocardial stunning after a sequence of six 4-minute occlusion/4-minute reperfusion cycles (phase I) but also the extent of cell death (myocardial infarction) after a 30-minute coronary occlusion (phase II). The magnitude of these beneficial actions was essentially equivalent to that observed after ischemic PC. The reduction in infarct size was accompanied by enhanced recovery of contractile function in the surviving myocardium, and again, the magnitude of this salutary effect was equivalent to that observed after ischemic PC. The ability of DETA/NO and SNAP to induce a late PC effect cannot be ascribed to myocardial ischemia secondary to a decrease in arterial pressure or an increase in heart rate, because neither NO donor produced any appreciable hemodynamic change; accordingly, the late PC effect must have been the result of a direct action of NO on the heart. Finally, the ability of NO donors to induce delayed protection against both stunning and infarction was completely abrogated by the concomitant administration of the antioxidant MPG, indicating that the mechanism whereby NO induces late PC involves the generation of oxidant species, such as ONOO- and/or ·OH.
Previous studies have demonstrated beneficial actions of NO precursors or NO donors in various models of acute ischemia in which the agents were present during ischemia and/or reperfusion.25 26 27 28 29 To our knowledge, this is the first study to indicate (1) that treatment with NO donors elicits a cardioprotective effect at a distance of 24 hours and (2) that NO donors induce this late PC effect via formation of oxidant species. This is also the first study to determine that a form of therapy widely used in patients elicits a late PC effect. Prior findings indicating that the development of the late phase of ischemic PC was blocked by NOS inhibitors had provided indirect evidence that this phenomenon is triggered by NO.3 4 The present finding that the effects of the late phase of ischemic PC can be mimicked by the administration of NO donors provides direct evidence that NO in itself is sufficient to elicit this cardioprotective mechanism without the concurrent perturbations associated with ischemia/reperfusion.
Methodological Considerations
All of the studies reported herein were performed in conscious
animals in an effort to rigorously test the potential cardioprotective
actions of NO donors under conditions that are as
physiological as possible. Open-chest animal
preparations are associated with a number of factors (such as
anesthesia, surgical trauma, fluctuations in temperature,
elevated catecholamine levels, abnormal
hemodynamics, and exaggerated formation of ROS) that
may interfere with myocardial stunning,18 20 with
myocardial infarction,21 and/or with
ischemic PC.19 22 Moreover, since the
focus of the present study was to examine the role of NO in
triggering late PC, we felt that it was important to eliminate
experimental conditions that may modulate the activity of NOS. For
example, the trauma and the inflammatory reaction associated with a
thoracotomy may promote the release of cytokines, which in turn
could induce iNOS activity. In this regard, Hoshida et
al30 found in dogs that the myocardial content of
manganese superoxide dismutase in the nonischemic (control)
region increased significantly 24 hours after a thoracotomy, possibly
as a result of the release of cytokines in the initial hours
after surgery. Also, surgical exposure of the brain has been found to
induce iNOS in cerebral tissue even in the absence of
ischemia.31 Since transcription of the
iNOS gene is controlled in part by antioxidant-sensitive
transcription factors (eg, nuclear factor-
B), the excessive
formation of ROS in open-chest animals18 could
also contribute to artifactual iNOS induction in these models.
To exclude the possibility that DETA/NO or SNAP could elicit PC by
causing myocardial ischemia as a result of hypotension and/or
tachycardia, we used doses that had no discernible
hemodynamic effects. To obtain another index of infarct
size limitation that is independent of tetrazolium staining, in phase
II we also measured the recovery of WTh, which essentially
paralleled the changes in infarct size (Figure 11). To minimize the
possibility that the cardioprotection observed in NO donor–pretreated
rabbits could be due to nonspecific actions, we examined 2 structurally
unrelated agents. DETA/NO is a relatively long-acting NO donor that
spontaneously and nonenzymatically releases NO with predictable
first-order kinetics.32 33 SNAP is a widely used
NO donor that lacks tolerance-producing
effects.24 The finding that the effects of
DETA/NO and SNAP were essentially identical, both in the setting of
myocardial stunning (Figures 5 and 6) and in the setting of myocardial
infarction (Figures 9 to 11), makes it very unlikely that the
protection was caused by moieties of the DETA/NO or SNAP molecule other
than NO itself. We elected to use DETA/NO and SNAP to avoid some of the
problems associated with other NO donors. For example,
3-morpholinosydnonimine generates both NO and
·O2-, which would make it
impossible to examine the role of NO in itself in triggering late PC.
Sodium nitroprusside is a widely used NO donor, but the toxicity
associated with the formation of cyanide could confound the results.
Furthermore, unlike other NO donors, neither DETA/NO nor SNAP is
dependent on the enzymatic release of
NO.24 32 33
NO as a Trigger of Late PC
Previous studies have demonstrated that administration of NOS
inhibitors during an ischemic stress blocks the
development of late PC against both myocardial
stunning3 and myocardial
infarction.4 Although these results implicate NO
as the trigger of the late phase of ischemic PC, the evidence
is indirect. Nonspecific actions of L-NA (the NOS inhibitor
used in these studies3,4) cannot be ruled out.
Furthermore, it is now apparent that NOS generates not only NO but also
·O2- and that the relative
proportions of these 2 radicals depend on the availability of substrate
(L-arginine) and cofactors (such as
tetrahydrobiopterin).8 9 10 For example, recent
studies have shown that when skeletal muscle is subjected to acute
ischemia, the main product of NOS is
·O2- rather than
NO.9 If the same occurs during acute myocardial
ischemia, NOS may trigger the development of late PC by
generating ·O2-, not by
generating NO. In this hypothetical scenario, the ability of L-NA to
block late PC3 4 would reflect the inhibition of
NOS-mediated formation of
·O2- rather than NO. To
elucidate this issue, we administered NO donors in the absence of
ischemia (and, consequently, in the absence of any changes in
·O2- formation associated
with ischemia). Our finding that both DETA/NO and SNAP induced
a late PC effect indistinguishable from that observed after
ischemic PC indicates that NO in itself can trigger this
phenomenon, without the need for a concomitant increase in
·O2- formation. Thus,
increased availability of NO is sufficient to activate cellular
adaptive mechanisms that result in increased resistance of the heart to
ischemia/reperfusion injury 24 hours later.
Mechanism of NO-Induced Late PC
There are several potential mechanisms whereby increased
biosynthesis of NO could elicit the development of a cardioprotective
effect 24 hours later (reviewed in Reference 33 ). In the present
study, we postulated that NO induces late PC via formation of
NO-derived ROS (eg, ONOO-). To test this
hypothesis, we administered DETA/NO in conjunction with MPG, a
cell-permeant antioxidant that reacts avidly with both
ONOO– and ·OH by virtue of its thiol
group.16 17 Since ONOO-
can decompose to form ·OH or ·OH-like
species,16 we reasoned that the administration of
MPG would be useful to interrogate the ROS pathway as a mechanism for
NO-induced late PC. Our results demonstrate that MPG completely
eliminated the late PC effect induced by DETA/NO, both in the setting
of myocardial stunning (Figure 7) and in the setting of myocardial
infarction (Figures 9 to 11). It seems highly unlikely that the
abrogation of late PC by MPG could have been mediated by a direct
reaction of MPG with either DETA/NO or NO, since MPG had no effect on
DETA/NO-induced vasodilation (Figure 3). Accordingly, these results
strongly suggest that NO elicits late PC via formation of ROS, most
likely ONOO- and/or ·OH.
This conclusion would explain the fact that the late phase of ischemic PC can be blocked both by inhibiting NOS3 4 and by scavenging ROS.23 34 This concept is also consistent with the notion that the development of late PC involves the activation of protein kinase C,6 35 36 since it is well established that ROS can stimulate this family of enzymes.37 It should be noted that MPG also prevents the development of late PC against stunning after six 4-minute occlusion/4-minute reperfusion cycles in our conscious rabbit model.34 The ability of MPG to block both ischemia-induced late PC and NO-induced late PC supports a common mechanism for these 2 phenomena. We therefore propose that the mechanism of late PC after an ischemic stimulus involves increased formation of NO, which reacts with ·O2- to form ONOO- and ·OH and that ONOO- and/or ·OH activates a PKC-mediated signal transduction cascade that culminates in the development of a protective effect 24 hours later.
Clinical Implications
Although the late phase of ischemic PC has been shown to
provide significant and sustained protection against myocardial
stunning and infarction, no widely applicable pharmacological treatment
has thus far been developed that can reproduce this
endogenous cardioprotective effect in patients with
coronary artery disease. Most agents that elicit a late
PC–like protection are not clinically applicable, for various reasons.
In contrast, NO donors (ie, nitrates) are widely used clinically. Our
finding that a relatively brief treatment with NO donors can induce a
long-lasting cardioprotective effect raises the intriguing possibility
that these agents, in addition to their well-known beneficial
hemodynamic actions, may also precondition the heart
against subsequent ischemic injury occurring at a distance of
hours or days. If this concept is confirmed in patients and if the
ability of nitrates to induce late PC is not hampered by the
development of tolerance, investigations would be warranted to identify
appropriate dosages and treatment modalities that could be used to
maintain a protracted preconditioned state.
Conclusions
Because the protection afforded by the late phase of
ischemic PC is sustained (3 to 4 days),11
pharmacological agents capable of mimicking this phenomenon ("late PC
mimetics") could have significant therapeutic value. The present
study demonstrates that 2 unrelated NO donors produce effective
protection against both reversible and irreversible injury during
myocardial ischemia/reperfusion in the absence of any
hemodynamic changes and that the magnitude of this
protection is equivalent to that afforded by ischemic PC.
Accordingly, administration of appropriate doses of NO donors could be
a useful clinical approach to the protection of the ischemic
myocardium. In addition, the present study provides new
insights into the mechanism of ischemic PC by indicating that
NO in itself can induce late PC and that it acts via formation of
secondary oxidant species.
|
Selected Abbreviations and Acronyms |
|---|
|
-nitro-L-arginine
|
Acknowledgments |
|---|
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, Wen-Jian Wu, and Gregg Shirk for expert technical assistance and Trudy Keith for expert secretarial assistance.
Received December 16, 1997; accepted April 15, 1998.
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 G. E. Nilsson and G. M. C. Renshaw Hypoxic survival strategies in two fishes: extreme anoxia tolerance in the North European crucian carp and natural hypoxic preconditioning in a coral-reef shark J. Exp. Biol., August 15, 2004; 207(18): 3131 - 3139. [Abstract] [Full Text] [PDF]
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Q. Qin, X.-M. Yang, L. Cui, S. D. Critz, M. V. Cohen, N. C. Browner, T. M. Lincoln, and J. M. Downey Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H712 - H718. [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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M. Loubani, A. Hassouna, and M. Galinanes Delayed preconditioning of the human myocardium: signal transduction and clinical implications Cardiovasc Res, February 15, 2004; 61(3): 600 - 609. [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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 R. Tissier, K. Aouam, A. Berdeaux, and B. Ghaleh Evidence for a Ceiling of Cardioprotection with a Nitric Oxide Donor-Induced Delayed Preconditioning in Rabbits J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 528 - 531. [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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 J. Vaage and G. Valen Preconditioning and cardiac surgery Ann. Thorac. Surg., February 1, 2003; 75(2): S709 - 714. [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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K. Laude, C. Thuillez, and V. Richard Peroxynitrite triggers a delayed resistance of coronary endothelial cells against ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1418 - H1423. [Abstract] [Full Text] [PDF]
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K. Laude, P. Beauchamp, C. Thuillez, and V. Richard Endothelial protective effects of preconditioning Cardiovasc Res, August 15, 2002; 55(3): 466 - 473. [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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R. Domenech, P. Macho, H. Schwarze, and G. Sanchez Exercise induces early and late myocardial preconditioning in dogs Cardiovasc Res, August 15, 2002; 55(3): 561 - 566. [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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E. Novalija, S. G. Varadarajan, A. K. S. Camara, J. An, Q. Chen, M. L. Riess, N. Hogg, and D. F. Stowe Anesthetic preconditioning: triggering role of reactive oxygen and nitrogen species in isolated hearts Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H44 - H52. [Abstract] [Full Text] [PDF]
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T. Csont, C. Csonka, A. Onody, A. Gorbe, L. Dux, R. Schulz, G. F. Baxter, and P. Ferdinandy Nitrate tolerance does not increase production of peroxynitrite in the heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H69 - H76. [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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 Z. Balafanova, R. Bolli, J. Zhang, Y. Zheng, J. M. Pass, A. Bhatnagar, X.-L. Tang, O. Wang, E. Cardwell, and P. Ping Nitric Oxide (NO) Induces Nitration of Protein Kinase Cepsilon (PKCepsilon ), Facilitating PKCepsilon Translocation via Enhanced PKCepsilon -RACK2 Interactions. A NOVEL MECHANISM OF NO-TRIGGERED ACTIVATION OF PKCepsilon J. Biol. Chem., April 19, 2002; 277(17): 15021 - 15027. [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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R. M Bell, C. C.T Smith, and D. M Yellon Nitric oxide as a mediator of delayed pharmacological (A1 receptor triggered) preconditioning; is eNOS masquerading as iNOS? Cardiovasc Res, February 1, 2002; 53(2): 405 - 413. [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. 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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M. A. Leesar, M. F. Stoddard, B. Dawn, V. G. Jasti, R. Masden, and R. Bolli Delayed Preconditioning-Mimetic Action of Nitroglycerin in Patients Undergoing Coronary Angioplasty Circulation, June 19, 2001; 103(24): 2935 - 2941. [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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M. S. Finkel Nitric Oxide and Viral Cardiomyopathy Circulation, October 31, 2000; 102(18): 2162 - 2164. [Full Text] [PDF]
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R. R. Morrison, R. Jones, A. M. Byford, A. R. Stell, J. Peart, J. P. Headrick, and G. P. Matherne Transgenic overexpression of cardiac A1 adenosine receptors mimics ischemic preconditioning Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1071 - H1078. [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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H. Tong, W. Chen, C. Steenbergen, and E. Murphy Ischemic Preconditioning Activates Phosphatidylinositol-3-Kinase Upstream of Protein Kinase C Circ. Res., August 18, 2000; 87(4): 309 - 315. [Abstract] [Full Text] [PDF]
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R. K. Kudej, S.-J. Kim, Y.-T. Shen, J. B. Jackson, A. B. Kudej, G.-P. Yang, S. P. Bishop, and S. F. Vatner Nitric oxide, an important regulator of perfusion-contraction matching in conscious pigs Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H451 - H456. [Abstract] [Full Text] [PDF]
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A. Dana, A. K. Jonassen, N. Yamashita, and D. M. Yellon Adenosine A1 Receptor Activation Induces Delayed Preconditioning in Rats Mediated by Manganese Superoxide Dismutase Circulation, June 20, 2000; 101(24): 2841 - 2848. [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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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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N. Sasaki, T. Sato, A. Ohler, B. O’Rourke, and E. Marban Activation of Mitochondrial ATP-Dependent Potassium Channels by Nitric Oxide Circulation, February 1, 2000; 101(4): 439 - 445. [Abstract] [Full Text] [PDF]
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Y. Takeishi, J.-i. Abe, J.-D. Lee, H. Kawakatsu, R. A. Walsh, and B. C. Berk Differential Regulation of p90 Ribosomal S6 Kinase and Big Mitogen-Activated Protein Kinase 1 by Ischemia/Reperfusion and Oxidative Stress in Perfused Guinea Pig Hearts Circ. Res., December 3, 1999; 85(12): 1164 - 1172. [Abstract] [Full Text] [PDF]
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 M. Taglialatela, A. Pannaccione, S. Iossa, P. Castaldo, and L. Annunziato Modulation of the K+ Channels Encoded by the Human Ether-a-Gogo-Related Gene-1 (hERG1) by Nitric Oxide Mol. Pharmacol., December 1, 1999; 56(6): 1298 - 1308. [Abstract] [Full Text]
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S. Banerjee, X.-L. Tang, Y. Qiu, H. Takano, S. Manchikalapudi, B. Dawn, G. Shirk, and R. Bolli Nitroglycerin induces late preconditioning against myocardial stunning via a PKC-dependent pathway Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2488 - H2494. [Abstract] [Full Text] [PDF]
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K. Shinmura, X.-L. Tang, H. Takano, M. Hill, and R. Bolli Nitric oxide donors attenuate myocardial stunning in conscious rabbits Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2495 - H2503. [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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C. J. Lowenstein NO news is good news PNAS, September 28, 1999; 96(20): 10953 - 10954. [Full Text] [PDF]
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 J. G. Wood, L. F. Mattioli, and N. C. Gonzalez Hypoxia causes leukocyte adherence to mesenteric venules in nonacclimatized, but not in acclimatized, rats J Appl Physiol, September 1, 1999; 87(3): 873 - 881. [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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S. Nuedling, S. Kahlert, K. Loebbert, P. A. Doevendans, R. Meyer, H. Vetter, and C. Grohe 17{beta}-Estradiol stimulates expression of endothelial and inducible NO synthase in rat myocardium in-vitro and in-vivo Cardiovasc Res, August 15, 1999; 43(3): 666 - 674. [Abstract] [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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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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D. J. Ing, J. Zang, V. J. Dzau, K. A. Webster, and N. H. Bishopric Modulation of Cytokine-Induced Cardiac Myocyte Apoptosis by Nitric Oxide, Bak, and Bcl-x Circ. Res., January 22, 1999; 84(1): 21 - 33. [Abstract] [Full Text] [PDF]
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T. M. Vondriska, J. Zhang, C. Song, X.-L. Tang, X. Cao, C. P. Baines, J. M. Pass, S. Wang, R. Bolli, and P. Ping Protein Kinase C {epsilon}-Src Modules Direct Signal Transduction in Nitric Oxide-Induced Cardioprotection : Complex Formation as a Means for Cardioprotective Signaling Circ. Res., June 22, 2001; 88(12): 1306 - 1313. [Abstract] [Full Text] [PDF]
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M. V. Cohen, X.-M. Yang, G. S. Liu, G. Heusch, and J. M. Downey Acetylcholine, Bradykinin, Opioids, and Phenylephrine, but not Adenosine, Trigger Preconditioning by Generating Free Radicals and Opening Mitochondrial KATP Channels Circ. Res., August 3, 2001; 89(3): 273 - 278. [Abstract] [Full Text] [PDF]
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