© 1997 American Heart Association, Inc.
Articles |
The Protective Effect of Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Is Mediated by Nitric Oxide Synthase
Evidence That Nitric Oxide Acts Both as a Trigger and as a Mediator of the Late Phase of Ischemic Preconditioning
From the Experimental Research Laboratory, Division of Cardiology, University of Louisville (Ky).
Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail rObollO1{at}ulkyvm.louisville.edu
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Abstract |
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Abstract Seventy-four conscious rabbits undergoing a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3) were assigned to nine groups. In group I (controls, n=8), the recovery of systolic wall thickening (WTh) after the sixth reperfusion was markedly improved on days 2 and 3 compared with day 1, indicating late preconditioning (PC) against myocardial stunning; the total deficit of WTh after the sixth reperfusion was reduced by 56% on day 2 and 50% on day 3 compared with day 1 (P<.01). Administration on day 2 of the nonselective NO synthase (NOS) inhibitor N
-nitro-L-arginine (L-NA)
(group II, n=8) or of the selective inducible NOS
inhibitors aminoguanidine (AG) (group IV, n=8) and
S-methylisothiourea sulfate (SMT) (group VI, n=6)
completely abrogated late PC against stunning on day 2. On day 3, the
expected PC effect became manifest in all groups. Administration of
L-NA, AG, or SMT on day 1 (groups III [n=7], V [n=6], and VII
[n=5], respectively) had no discernible effect on the deficit of WTh
on day 1, indicating that these agents do not augment the severity of
myocardial stunning in nonpreconditioned
myocardium. In group VIII (n=7), the abrogation of late PC
by SMT on day 2 was completely reversed by the concomitant
administration of L-arginine (595 mg/kg IV), indicating
that it was not due to nonspecific NOS-unrelated actions.
Administration of L-arginine alone on day 2 (group IX
[n=5]) had no effect on the deficit of WTh. Furthermore,
administration of L-NA on day 1 (group III) prevented the appearance of
the PC effect on day 2, whereas AG (group V) and SMT (group VI) did
not, suggesting that the development of late PC on day 1 is triggered
by the endothelial (type III) isoform of NOS. This
study demonstrates that three structurally different NOS
inhibitors (L-NA, AG, and SMT), given 24 hours after the PC
ischemia, consistently abrogate late PC against
myocardial stunning in conscious rabbits, indicating that this
cardioprotective effect is mediated by the activity of NOS. The results
obtained with AG and SMT specifically implicate the inducible (type II)
isoform as the mediator of the protection on day 2. Previous studies
have shown that NO triggers the development of late PC. The present
results indicate that NO plays a dual role in late PC against stunning,
acting initially as the trigger and subsequently as the mediator of
the protection.
Key Words: myocardial reperfusion • N-nitro-L-arginine • aminoguanidine • S-methylisothiourea sulfate • L-arginine
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Introduction |
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The cardioprotective effects of ischemic PC occur in two temporally distinct phases: an early phase, which develops immediately and wanes within 2 to 4 hours after the PC challenge,1–6 and a second (or late) phase, which begins after 12 to 24 hours and lasts for 3 to 4 days.7–16 Although recent evidence indicates that the development of late PC against myocardial stunning is triggered by the generation of NO14 and ROS12 during the initial ischemic challenge, the cellular mechanism(s) that mediates the protection against stunning 1 to 4 days later, during the second ischemic challenge, remains unknown.17 Identification of the mediator(s) of protection is among the most important, if not the most important, unresolved issues that currently limit our understanding of the late phase of ischemic PC.
One cellular mediator that could account for the beneficial effects of late PC on myocardial stunning is NO. NO or its second messenger, cGMP, has been shown to exert a number of actions that would be expected to be beneficial during myocardial ischemia, including antagonism of the effects of ß-adrenergic stimulation,18,19 inhibition of Ca2+ influx into myocytes,20,21 decrease in myocardial contractility,19,22–25 and reduction in myocardial oxygen consumption.26–29 The reduced Ca2+ current may alleviate the Ca2+ overload associated with acute myocardial ischemia, which is one of the major mechanisms of myocardial stunning.30 The antiadrenergic action and the decrease in oxygen consumption may preserve high-energy phosphates during ischemia, thereby minimizing cellular injury and enhancing postischemic recovery of contractility. The concept that NO protects against myocardial stunning is supported by the results of Hasebe et al,31 who found that inhibition of NO production with L-NA exacerbated myocardial stunning in conscious dogs independent of changes in myocardial blood flow and proposed that NO exerts a direct antistunning effect.
In the present study, we hypothesized that the protective effects of late PC against myocardial stunning are mediated by augmented NO formation secondary to ischemia-induced alterations of NOS gene expression. A large investigation was designed to test this hypothesis under conditions as physiological as possible. Using a well-characterized conscious rabbit model of late PC against myocardial stunning,14–16 we examined whether the protective effects of late PC were abolished by the administration of NOS inhibitors before the second ischemic challenge, 24 hours after the initial PC isch- emia. Three different inhibitors of NOS were tested. To determine whether late PC is mediated by NO synthesis, irrespective of the NOS isotype(s) involved, we examined the nonselective NOS inhibitor L-NA, which inhibits all three isoforms of the enzyme.32 To specifically investigate the role of iNOS, we also examined two selective iNOS inhibitors (AG33 and SMT34). To positively rule out the possibility of nonspecific actions of the NOS inhibitors used, we examined whether the inhibition of late PC by SMT could be reversed by the simultaneous administration of the NOS substrate, L-arginine. The study was conducted in conscious animals to eliminate the confounding effects of factors associated with open-chest preparations, such as anesthesia, surgical trauma, fluctuations in temperature, elevated catecholamines, excessive free radical formation, and release of cytokines, which could, in themselves, induce iNOS35 and also interfere with myocardial stunning36–38 or with PC.4,5,39,40 The results demonstrate that all three NOS inhibitors (L-NA, AG, and SMT) consistently abrogate late PC against stunning, implicating NOS as a mediator of the protection.
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Materials and Methods |
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Experimental Preparation
The experimental preparation has been described in detail previously14,15 and will be briefly summarized here. New Zea- land White male rabbits (weight, 2.8±0.1 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 chest wound was closed in layers, and a small tube was left in the thorax for 3 days to evacuate air and fluids postoperatively. Gentamicin was administered before surgery and on the first and second postoperative days (0.7 mg/kg IM each day). Rabbits were allowed to recover for a minimum of 10 days after surgery.
Experimental Protocol
Throughout the experiments, rabbits were kept in a cage in a
quiet dimly lit room. LV systolic WTh, range gate depth, and
the ECG were continuously recorded on a thermal array chart
recorder (Gould TA6000). No sedative or antiarrhythmic agents were
given at any time. The experimental protocol consisted of 3 consecutive
days of coronary artery occlusions (days 1, 2, and 3) (Fig 1
). On each day, the rabbits underwent a
sequence of six 4-minute coronary occlusions interspersed with
4 minutes of reperfusion. The performance of successful
coronary occlusions was verified by observing the development
of ST-segment elevation and changes in the QRS complex on the ECG and
the appearance of paradoxical systolic wall thinning on the
ultrasonic crystal recordings.
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Rabbits were assigned to nine groups (Fig 1
). Group I (control rabbits)
underwent the coronary occlusion/reperfusion protocol on days
1, 2, and 3 without any treatment. In group II, rabbits received an
intravenous infusion of L-NA before the first
coronary occlusion on day 2 (1.3 mg ·
kg-1 · min-1 for 10 minutes, starting
20 minutes before and ending 10 minutes before the first occlusion;
total dose, 13 mg/kg). L-NA (Sigma Chemical Co) was dissolved in
normal saline (total volume infused, 20 mL). In group III, rabbits
received L-NA according to the same protocol used in group II, except
that the treatment was given on day 1 instead of day 2. In group IV,
rabbits received a subcutaneous injection of AG (150 mg/kg) 1
hour before the first coronary occlusion on day 2. AG
hydrochloride (Aldrich Chemical Co) was dissolved in 2 mL of water,
and the pH of the solution was adjusted to 7.4 with 0.1N NaOH. In group
V, rabbits received the same dose of AG (150 mg/kg) 1 hour
before the first coronary occlusion on day 1. AG was given 1
hour before ischemia, because based on the slow onset of its
vascular actions41,42 and the increase in its potency with
time of preincubation,33,42,43 this compound is thought to
enter the intracellular space relatively slowly.32 In group
VI, rabbits underwent the six-cycle occlusion/reperfusion protocol with
no treatment on day 1. On day 2, they were given 10 consecutive
intravenous boluses of SMT (0.05 mg/kg over 30
seconds) every 8 minutes, starting 18 minutes before the first
coronary occlusion and ending 10 minutes after the sixth
reperfusion (total dose, 0.5 mg/kg). SMT sulfate (FW:278,
Aldrich Chemical Co) was dissolved in normal saline (0.5
mg/mL, pH 
6.0); the total volume injected was 0.1
mLx10xbody weight (2.8 mL). In group VII, rabbits were given SMT
according to the same protocol used in group VI, except that the
treatment was given on day 1 instead of day 2. In group VIII, rabbits
received SMT on day 2 as in group VI; in addition, on day 2 they were
given an intravenous infusion of L-arginine
starting 28 minutes before the first coronary occlusion and
ending 25 minutes after the sixth reperfusion (rate of infusion, 16
mg · kg-1 · min-1 for the first
10 minutes and then 5 mg · kg-1 ·
min-1 until the end of the infusion; total dose, 595
mg/kg). L-Arginine hydrochloride (Sigma) was
dissolved in normal saline (200 mg/mL, pH 7.4); the total volume
infused was 3 mL/kg. In group IX, rabbits were given
L-arginine on day 2 (same dose as in group VIII) without
SMT. The solutions of L-NA, AG, SMT, and L-arginine were
filtered through a 0.2-µm Millipore filter to ensure sterility. The
dose of L-NA was selected on the basis of our previous
experience,14 whereas the doses of AG, SMT, and
L-arginine were chosen on the basis of the pilot studies
reported below in "Results." At the conclusion of the study, the
rabbits were euthanized, and the size of the occluded/reperfused
coronary vascular bed was determined as
described.14
Measurement of Regional Myocardial Function
Regional myocardial function was assessed as systolic
thickening fraction using the pulsed Doppler probe, as previously
described.44 The beginning of systole was determined from
the peak of the QRS complex; the end of systole, from the notch
separating the larger (systolic) from the smaller
(diastolic) increase in thickness on the WTh tracings.
(Pilot studies using a high-fidelity Millar pressure transducer
demonstrated that the peak of the QRS complex corresponded exactly to
the onset of the rapid upstroke of LV pressure and that the notch in
the WTh tracing occurred within 2 milliseconds from the peak negative
LV dP/dt; in these studies, the measurements of WTh obtained using LV
pressure and dP/dt as a reference system were identical to those
obtained using the QRS complex and the notch in the WTh tracing.)
Percent systolic thickening fraction was calculated as the
ratio of net systolic thickening to end-diastolic
wall thickness, multiplied by 100.44 The total deficit of
systolic WTh after reperfusion (an integrative assessment of
the overall severity of myocardial stunning after the sixth
reperfusion) was calculated by measuring the area between the
systolic WTh-versus-time line and the baseline (100% line)
during the 5-hour recovery phase after the sixth
reperfusion.11–15,36,37 In all animals, measurements were
averaged from at least 10 beats at baseline and from at least five
beats at all subsequent time points.
Statistical Analysis
Data are reported as mean±SEM. For intragroup comparisons,
hemodynamic variables and WTh were analyzed
by a two-way repeated-measures ANOVA (time and day) to determine
whether there was a main effect of time, a main effect of day, or a
day-by-time interaction. If the global tests showed a significant main
effect or interaction, post hoc contrasts between different time points
on the same day or between different days at the same time point were
performed with Student's t tests for paired data, and the
resulting P values were adjusted according to the Bonferroni
correction. For intergroup comparisons, continuous variables were
analyzed by either a one-way or a two-way repeated-measures
(time and group) ANOVA, as appropriate, followed by unpaired Student's
t tests with the Bonferroni correction. All statistical
analyses were performed using the SAS software
system.45 Two-way ANOVA was performed using the procedure
GLM (General Linear Models).45
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Results |
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Exclusions
A total of 96 conscious rabbits were used in the present study (22 for the pilot studies and 74 for the studies of late PC). Of the 74 rabbits instrumented for the studies of late PC, 14 (19%) were excluded for the reasons specified in Table 1
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Pilot Studies
Pilot studies were conducted in 22 conscious rabbits to identify
doses of AG, SMT, and L-arginine that have no effect on
heart rate and arterial pressure. This was necessary for
two reasons: (1) since the severity of myocardial stunning is modulated
by afterload,38 changes in arterial pressure
would confound the assessment of recovery of function, and (2) the lack
of changes in arterial pressure after treatment with AG and
SMT would confirm that the doses used produce a selective inhibition of
iNOS with no effect on vascular eNOS. Arterial pressure was
measured by cannulating the ear dorsal artery with a 23-gauge
angiocatheter. The catheter was connected to a fluid-filled
high-sensitivity pressure transducer, which was connected to a pressure
analyzer (model BPA-109 Micro-Med).
In 3 rabbits, a dose of 100 mg/kg of AG given intravenously over 5 minutes caused a sustained (>2-hour) decrease in heart rate and arterial pressure (the decrease in heart rate was abolished by atropine [data not shown]). In contrast, in 3 other rabbits, 150 mg/kg of AG given subcutaneously caused no change in heart rate (239±27 bpm before AG versus 236±26 bpm at 5 minutes, 248±18 bpm at 1 hour, and 253±23 bpm at 3 hours after AG), mean arterial pressure (89±3 mm Hg before AG versus 86±4 mm Hg at 15 minutes, 88±3 mm Hg at 1 hour, and 86±3 mm Hg at 3 hours after AG), or systolic thickening fraction (30.4±3.2% before AG versus 29.5±3.0% at 5 minutes, 29.8±2.9% at 15 minutes, 31.0±4.3% at 1 hour, and 31.1±3.8% at 3 hours after AG). Consequently, this dose of AG was chosen for the present experiments.
In 8 rabbits, decreasing doses of SMT were injected intravenously over 30 seconds (0.5, 0.1, 0.075, and 0.05 mg/kg). The highest dose that did not change heart rate or arterial pressure was 0.05 mg/kg (higher doses increased arterial pressure). At higher doses, it was found that the hemodynamic effects of all bolus doses of SMT subsided completely within 5 to 10 minutes, suggesting that the inhibition of NOS by this agent dissipates quickly in the conscious rabbit. Because of this short duration of action of SMT, we designed a protocol in which 10 hemodynamically inactive doses of SMT (0.05 mg/kg each) were injected intravenously at 8-minute intervals (the rationale was to produce continuous inhibition of iNOS for at least 80 minutes [an interval that would cover the entire sequence of six 4-minute occlusion/4-minute reperfusion cycles] without causing hemodynamic changes). In 3 other rabbits treated according to this protocol, SMT had no appreciable hemodynamic effect; eg, mean arterial pressure averaged 77 mm Hg before SMT and 76 mm Hg at 30 minutes, 75 mm Hg at 1 hour, and 75 mm Hg at 3 hours after SMT, whereas thickening fraction averaged 41% before SMT and 42% at 30 minutes, 42% at 1 hour, and 43% at 3 hours after SMT. Consequently, this protocol for SMT administration was chosen for the present experiments.
Dose-ranging studies in 5 rabbits demonstrated that the highest intravenous infusion rate of L-arginine that could be administered in conjunction with our dosage of SMT without changing heart rate was 16 mg · kg-1 · min-1 for 10 minutes followed by 5 mg · kg-1 · min-1, starting 10 minutes before the first dose of SMT and ending 25 minutes after the sixth reperfusion (higher infusion rates caused an increase in heart rate). Consequently, this dose of L-arginine was chosen for the present experiments.
Postmortem Analysis
The size of the occluded/reperfused vascular bed was similar in
the nine groups: 1.18±0.14 g (20.6±1.8% of LV weight) in group I,
0.89±0.12 g (18.6±2.4%) in group II, 1.09±0.15 g (19.8±0.6%) in
group III, 1.24±0.22 g (21.3±2.1%) in group IV, 1.31±0.24 g
(21.7±2.2%) in group V, 1.15±0.33 g (19.7±3.5%) in group VI,
1.01±0.10 g (18.2±2.2%) in group VII, 1.17±0.31 g (19.7±3.4%) in
group VIII, and 1.14±0.46 g (20.3±7.2%) in group IX. Tissue staining
with triphenyltetrazolium chloride
demonstrated the absence of infarction in all of the rabbits included
in the final analysis. In all animals, the ultrasonic crystal
was found to be at least 3 mm from the boundaries of the
isch- emic/reperfused region.
Regional Myocardial Function
As shown in Table 2, in groups
II and III the administration of L-NA produced a sustained decrease in
heart rate that persisted up to 5 hours after the sixth reperfusion. As
a result, the heart rate was significantly lower on day 2 in group II
and on day I in group III compared with the corresponding values in
group I (control group) (Table 2). The decreases in heart rate elicited
by L-NA in groups II and III were similar (Table 2). On the days when
L-NA was not given, there were no appreciable differences in heart rate
among groups I, II, and III (Table 2). The heart rate did not differ
significantly in groups IV, V, VI, VII, VIII, and IX versus group I
during the sequence of coronary occlusion/reperfusion cycles or
during the 5-hour reperfusion period on day 1, 2, or 3 (Table 2).
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The measurements of baseline systolic thickening fraction on
days 1, 2, and 3 are summarized in the legends to Figs 2 to 10
;
there were no significant differences among the nine groups on the same
day or among different days within the same group. Compared with
baseline (pretreatment) values, the measurements of thickening fraction
obtained after treatment (immediately before the first coronary
occlusion [preocclusion values]) were virtually unchanged in all
groups (Figs 3 to 10), indicating that L-NA, AG, SMT, and
L-arginine had no significant effect on regional myocardial
function. The changes in thickening fraction associated with
coronary occlusion and reperfusion will be described first for
the control group and then for the treated groups.
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Group I (Control Group)
On day 1, thickening fraction remained significantly
(P<.05) depressed for 4 hours after the sixth reperfusion
and returned to values not significantly different from preocclusion
values by 5 hours (Fig 2). Thus, the sequence of six 4-minute
occlusion/4-minute reperfusion cycles resulted in severe myocardial
stunning that lasted, on average, 4 hours. On day 2, the recovery of
WTh was markedly improved throughout the first 4 hours of reperfusion
compared with day 1 (Fig 2). The total deficit of WTh after the sixth
reperfusion was 56% less on day 2 compared with day 1
(P<.01) (Figs 11 and 12). On day 3, the recovery of WTh
after the six 4-minute occlusions was again enhanced compared with day
1 and similar to that observed on day 2 (Fig 2); the total deficit of
WTh was 50% less compared with day 1 (P<.01) (Figs 11 and 12). Thus, myocardial stunning was attenuated markedly, and to a
similar extent, on days 2 and 3 compared with day 1.
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Group II (L-NA–Treated Group)
On day 1, both the thickening fraction (Fig 3) and the total
deficit of WTh (Figs 11 and 12) were comparable to those observed in
the control group. On day 2, however, the results were quite different:
unlike the pattern observed in control rabbits, in L-NA–treated
rabbits the recovery of WTh during the 5-hour final reperfusion period
was not improved compared with day 1 (Fig 3), so that the total deficit
of WTh did not differ significantly from that observed on day 1 (Figs 11 and 12). The total deficit of WTh on day 2 was 103% greater than
the corresponding value in control rabbits (P<.01) and was
similar to that observed in control rabbits on day 1 (Figs 11 and 12).
On day 3, however, the recovery of WTh in L-NA–treated rabbits was
markedly improved compared with day 2 (Fig 3) and was similar to that
noted on day 3 in the control group (Fig 2). The total deficit of WTh
was 49% less than that observed on day 2 in the same animals
(P<.01) and was comparable to that noted on day 3 in
control rabbits (Figs 11 and 12). Thus, administration of L-NA on day 2
completely abrogated the protective effect of late PC; when L-NA was
not administered (day 3), a full PC effect became apparent.
Group III (L-NA–Pretreated Group)
These rabbits received L-NA as in group II, except that the
agent was administered on day 1 instead of day 2. On day 1, there were
no differences in the recovery of WTh during the 5 hours of reperfusion
between this group and the control group (Fig 4); accordingly, the
total deficit of WTh after the sixth reperfusion was comparable to that
observed in control rabbits on day 1 (Figs 11 and 12).
Consistent with our previous results,14 the
thickening fraction and the total deficit of WTh remained essentially
unchanged on day 2 vis-à-vis day 1 (Figs 11 and 12), indicating
that L-NA prevented the development of late PC. On day 3, the expected
PC effect became apparent (Figs 4, 11, and 12). Thus, administration of
L-NA on day 1 did not augment the severity of myocardial stunning on
the same day, indicating that the absence of late PC against stunning
observed on day 2 in group II reflects a specific inhibition of the PC
effect, not an inherent detrimental action of L-NA on myocardial
stunning.
Groups IV (AG-Treated Group) and VI (SMT-Treated Group)
Similar to the results obtained in group II, in groups IV and VI
the recovery of WTh after the sixth reperfusion on day 2 was not
improved compared with day 1 (Figs 5 and 7); as a result, the total
deficit of WTh on day 2 was not less than that observed on day 1 (Figs 11 and 12). On day 3, however, the recovery of WTh in groups IV and VI
was significantly faster than on day 2 (Figs 5 and 7), and the deficit
of WTh was 64% and 58% less, respectively, than that noted on day 2
(P<.01) (Figs 11 and 12). Thus, late PC against stunning
was completely abrogated by AG and SMT on day 2 but was fully expressed
in the absence of AG and SMT on day 3.
Groups V (AG-Pretreated Group) and VII (SMT-Pretreated Group)
These rabbits received AG or SMT as in groups IV and VI,
respectively, except that the drug was given on day 1 instead of day 2.
On day 1, the recovery of WTh during the 5 hours of reperfusion was
similar to that observed on day 1 in the control group (Figs 6 and 8),
so that the total deficit of WTh after the sixth reperfusion did not
differ significantly from that observed in control rabbits on day 1
(Figs 11 and 12). On days 2 and 3, the recovery of WTh was
significantly improved compared with day 1 (Figs 6 and 8), and the
total deficit of WTh was comparable to that observed on days 2 and 3 in
control rabbits (Figs 11 and 12). Thus, similar to the results obtained
with L-NA, administration of AG or SMT on day 1 did not exacerbate the
severity of myocardial stunning on the same day, indicating that the
absence of late PC against stunning observed on day 2 in groups IV and
VI reflects a specific inhibition of the PC effect, not an inherent
deleterious action of AG or SMT on the postischemic
recovery of myocardial contractility. It should also be
noted that the inability of AG and SMT to prevent late PC in groups V
and VII, in contrast to the effects of L-NA in group III, further
supports their selectivity for iNOS: if either AG or SMT had inhibited
eNOS on day 1, it should have blocked the development of late PC, as
was observed with L-NA.
Group VIII (SMT+L-Arginine–Treated Group)
This group was studied to rule out the possibility that the
inhibition of late PC against stunning effected by SMT in group VI may
have been caused by nonspecific actions of SMT on enzymes other than
NOS. On day 2, rabbits received SMT (same dose as in group VI) in
conjunction with L-arginine. On day 1, there were no
differences in the recovery of WTh between this group and the control
group (Figs 9, 11, and 12). In contrast to group VI, however, on day 2
the recovery of WTh in group VIII was significantly faster than on day
1 (Fig 9), and the total deficit of WTh was comparable to that observed
on day 2 in control rabbits (Figs 11 and 12). On day 3, the recovery of
WTh was similar to that observed on day 2 (Figs 9, 11, and 12). Thus,
in contrast to group VI, in which administration of SMT abrogated late
PC on day 2, in group VIII the administration of SMT in conjunction
with L-arginine had no effect on late PC against stunning
on day 2.
Group IX (L-Arginine–Treated Group)
This group was studied to rule out the possibility that
L-arginine in itself alleviated myocardial stunning on day
2 independent of SMT (if this were the case, the attenuation of
stunning observed on day 2 in group VIII could be construed as the
result of an intrinsic beneficial action of L-arginine on
stunning rather than a specific consequence of the antagonism of SMT by
L-arginine). On day 2, rabbits received
L-arginine (same dose as in group VI) without SMT. There
were no differences in the recovery of WTh between group IX and the
control group on days 1, 2, and 3 (Figs 10, 11, and 12). Thus,
administration of L-arginine on day 2 had no beneficial
effect on myocardial stunning on the same day, indicating that the
presence of late PC against stunning on day 2 in group VI was not
caused by an inherent beneficial action of L-arginine on
the postischemic recovery of myocardial
contractility.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Salient Findings
The major finding of the present study is that three different NOS inhibitors (L-NA, AG, and SMT), given 24 hours after the PC ischemia (day 2), completely and consistently eliminated the protection afforded by late PC against myocardial stunning in conscious rabbits. This effect was not due to an inherent detrimental action of L-NA, AG, or SMT on myocardial stunning, as none of the agents had any adverse influence on postischemic dysfunction in nonpreconditioned myocardium (ie, when given on day 1); they exacerbated stunning only in preconditioned myocardium (ie, when given on day 2). Furthermore, this effect was not due to unfavorable changes in heart rate or arterial pressure, as these variables were not modified by our doses of L-NA, AG, and SMT (the only exception was the decrease in heart rate after L-NA, which, however, cannot account for the abrogation of late PC in group II, as elaborated below). Finally, this effect was not due to nonspecific actions on enzymes other than NOS, as the inhibition of late PC by SMT was completely reversed by the concomitant administration of L-arginine. Taken together, the present results demonstrate that the activity of NOS 24 hours after the initial ischemic challenge is necessary for late PC against myocardial stunning to become manifest in the conscious rabbit. The results obtained with AG and SMT specifically implicate iNOS as the mediator of the protection, although it is recognized that positive identification of the isoform(s) involved cannot be achieved solely with pharmacological studies.
To our knowledge, this is the first demonstration that the cardioprotection afforded by the late phase of isch- emic PC is mediated by NOS. Previous studies14 have shown that generation of NO during the initial ischemia on day 1 triggers the development of the PC response observed 24 hours later in this conscious rabbit model. The present results indicate that the role of NO in late PC against stunning is considerably more complex, since this radical appears to have a dual function, as a trigger as well as a mediator of the protection.
Methodological Considerations
The use of a conscious animal preparation was felt to be
particularly important for the present study because the trauma and
inflammatory reaction associated with a thoracotomy may elicit the
release of cytokines, which in turn could induce iNOS activity.
In this regard, Hoshida et al46 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 following surgery. Also,
surgical exposure of the brain has been found to induce iNOS in
cerebral tissue even in the absence of isch- emia.35
In addition, the generation of ROS after myocardial
ischemia/reperfusion is exaggerated in open-chest animal
preparations,37 which could conceivably lead to
exaggerated, or perhaps even artifactual, induction of iNOS via
ROS-mediated activation of nuclear factor-
B or protein kinase
C.47
Experiments With L-NA
L-NA, a nonselective inhibitor of all three NOS
isoforms,32 was used to address the fundamental question of
this investigation: Does NO (irrespective of its source) contribute to
the protective effects of late PC against myocardial stunning? The dose
of L-NA used in the present study (13 mg/kg) was chosen
because it has been shown to inhibit NOS activity by
>70%48 and to markedly decrease exhaled NO (measured by
chemiluminescence) in rabbits.49 We14 have
previously found that this dose produces no demonstrable alterations of
arterial pressure but markedly suppresses
acetylcholine-induced vasodilation in conscious rabbits, suggesting
that it does not decrease basal endothelial NO release,
although it is sufficient to block increased eNOS activity. The fact
that L-NA completely abrogated late PC in group II demonstrates that
the protection against stunning is mediated by the activity of NOS,
although this result, in itself, does not enable one to identify which
NOS isoform(s) is involved. The decrease in heart rate induced by L-NA
in groups II and III is consistent with previous
results14,49,50 and is thought to reflect the central
regulatory function of NO on the sympathetic and parasympathetic
tone.49 The effect of L-NA on heart rate cannot explain the
abrogation of late PC in group II for several reasons: (1) a decrease
in heart rate, if anything, would be expected to ameliorate myocardial
stunning by augmenting total diastolic time and, therefore,
preload38; (2) the decrease in heart rate was similar on
day 2 in group II and on day 1 in group III (Table 2), yet L-NA had no
effect on myocardial stunning on day 1 in group III; and (3) the same
abrogation of late PC that was induced by L-NA in group II was also
induced by AG in group IV and by SMT in group VI, yet neither AG nor
SMT had any effect on heart rate (Table 2).
Experiments With AG and SMT
Two inhibitors of iNOS, AG and SMT, were then used to
specifically interrogate the role of this isozyme. The rationale for
using two different iNOS inhibitors was to minimize the
possibility that the effects observed would be due to a nonspecific
action of either agent. AG and SMT were chosen because among the NOS
inhibitors currently available, AG has the highest
selectivity for iNOS,32,34,51 whereas SMT has the highest
potency for this enzyme.34 Using assays for NOS activity,
AG has been shown to have an IC50 of 160.0
µmol/L for the constitutive isoform of NOS versus 5.4
µmol/L for iNOS.33,51 This relative selectivity is
confirmed by the fact that AG is 40 times less effective than
NG-monomethyl-L-arginine in
increasing arterial blood pressure in vivo.52
As detailed in "Results" ("Pilot Studies"), the dose of AG used
in the present study had no effect on arterial blood
pressure, suggesting that it did not inhibit NO production by
vascular eNOS.
Although the results obtained with AG in group IV implicate iNOS as a mediator of late PC against stunning, AG has been found to have other effects as well, including (among other) inhibition of histamine metabolism, polyamine catabolism, aldose reductase, catalase, and other copper- or iron-containing enzymes (reviewed in Reference 3232 ). Accordingly, we decided to test the role of iNOS in late PC by using an unrelated iNOS inhibitor. We elected to use SMT, a recently described S-substituted isothiourea.34,53 SMT is a more potent inhibitor of iNOS than any other known NOS inhibitor and is 10 to 30 times selective for iNOS compared with eNOS.34 Importantly, SMT does not inhibit the activity of xanthine oxidase, diaphorase, lactate dehydrogenase, monoamine oxidase (histaminase), catalase, cytochrome P450, or superoxide dismutase and, therefore, is devoid of many of the nonspecific actions of AG.34 As in the case of AG, SMT has been found to exert beneficial effects in a number of pathological conditions in which iNOS has been implicated (reviewed in Reference 3232 ). Our pilot studies (reported in "Results") demonstrate that the dosage of SMT selected for the present investigation did not change arterial pressure, suggesting that it did not affect vascular eNOS.
When this dosage was tested in our protocol of late PC, it produced essentially the same results as those obtained with AG; ie, it had no effect when given on day 1 (group VII), but it completely abolished the protection against stunning when given on day 2 (group VI). Because AG and SMT belong to two chemically different groups of NOS inhibitors32 and because SMT does not share the aforementioned nonspecific (NOS-unrelated) actions of AG, it seems very unlikely that the results obtained with both compounds were due to a nonspecific effect. Therefore, the finding that both AG and SMT blocked late PC in the same manner (groups IV and VI) supports a role of iNOS in the protective effects of late PC against myocardial stunning.
Nevertheless, to positively rule out the possibility that the inhibition of late PC by iNOS inhibitors may have been caused by nonspecific mechanisms, we tested whether such an inhibition could be reversed by L-arginine. Because SMT acts as a competitive inhibitor of iNOS at the L-arginine site,34 its effects on iNOS should be abolished by an excess of L-arginine. Indeed, our data demonstrate that when SMT was administered in conjunction with L-arginine (group VIII), late PC against stunning was no longer attenuated. The fact that the inhibitory effect of SMT on late PC was completely blocked by L-arginine confirms that it was specifically due to inhibition of NOS activity (as opposed to hypothetical NOS-unrelated actions). The fact that L-arginine in itself had no effect on late PC against stunning (group IX) confirms that the alleviation of stunning effected by L-arginine in group VIII on day 2 was due to antagonism of SMT (as opposed to hypothetical SMT-unrelated actions).
It must be stressed that the primary goal of the present study was to determine whether NOS activity in general mediates late PC against stunning, not to identify the NOS isoform(s) involved. Although the results obtained in groups IV, V, VI, VII, VIII, and IX strongly support the conclusion that the protection afforded by late PC against myocardial stunning on day 2 is mediated primarily by iNOS, the possibility that eNOS may also contribute to the beneficial effects of late PC cannot be ruled out on the basis of pharmacological data. A possible role of this enzyme is supported by the recent findings of Kim et al,54 who have shown that in conscious dogs a 10-minute coronary occlusion induces a delayed increase in the coronary flow response to endothelium-dependent vasodilators, as well as an increase in the cardiac production of NO, indicating upregulation of coronary eNOS. Unequivocal identification of the specific isoforms of NOS that are responsible for late PC will require a molecular approach, ie, the use of transgenesis and gene targeting to manipulate the individual NOS genes in animal models of ischemic PC.
The Dual Role of NO in Late PC
In a previous study,14 we found that
administration of L-NA on day 1 prevented late PC against myocardial
stunning, indicating that the development of the cardioprotective
response is triggered by the generation of NO during the initial
ischemic challenge. (These results were confirmed in group III
in the present study.) The present finding that administration
of L-NA on day 2 abrogates late PC against stunning (group II) expands
our previous results by demonstrating that NO also serves as the
mediator of the beneficial effects of late PC. Thus, NO plays two
different roles in late PC: on day 1, it initiates the development of
the cardioprotective mechanism, whereas on day 2, it protects against
myocardial stunning.
Because L-NA is a nonselective NOS inhibitor, in our previous study14 it was not possible to make any conclusions regarding which isoform of NOS is involved in the initiation of the protective response on day 1 (ie, eNOS versus iNOS). In theory, either isoform could be a source of NO during the PC ischemia, since cardiac myocytes and endothelial cells constitutively express eNOS25 and recent reports55,56 have demonstrated that Ca2+-independent NOS activity (presumably iNOS) is also present in normal rabbit myocardium. The present study provides new insights into this issue. The finding that in contrast to L-NA (group III) neither of the selective iNOS inhibitors (AG and SMT) prevented the development of late PC when given on day 1 (groups V and VII, respectively) strongly suggests that the enzyme responsible for generating the NO that triggers late PC on day 1 is eNOS, not iNOS. Accordingly, it would appear that two different NOS isoforms participate in the pathophysiology of late PC: eNOS in triggering the response and iNOS in mediating the subsequent protection.
Previous Studies of the Role of iNOS in Late PC
No previous investigation has examined the role of NOS as a
mediator of the late phase of ischemic PC. Vegh et
al57 assessed the severity of ventricular
arrhythmias during a 25-minute coronary occlusion in
open-chest dogs subjected, 20 hours earlier, to four 5-minute periods
of rapid cardiac pacing (220 bpm). They found that pacing markedly
reduced the severity of arrhythmias and that this protective
effect was abolished by pretreatment with dexamethasone.
Since dexamethasone blocks the expression of both iNOS and
cyclooxygenase, the authors concluded that either
iNOS or cyclooxygenase was involved in the observed
antiarrhythmic effects. However, steroids exert a vast number of
actions, so the effects of dexamethasone may have been
mediated by other mechanisms as well. There are numerous differences
between the present study and that of Vegh et al,57
including differences in models (conscious rabbits versus open-chest
dogs), PC stimuli (ischemia versus pacing), and end points
(postischemic dysfunction versus arrhythmias), all
of which preclude direct comparisons. For example, it is unknown
whether ischemia elicits a delayed protection against
arrhythmias and, if so, whether the mechanism would be the same
as that of the delayed protection against myocardial stunning.
Recently, Zhao et al55 have reported that pretreatment with
monophosphoryl lipid A in open-chest rabbits induces a delayed
protection against infarction 24 hours later, which is associated with
a 25% to 50% increase in iNOS activity and can be blocked by AG.
These results suggest that the salutary effects of pharmacological PC
with monophosphoryl lipid A are mediated by iNOS and therefore may
involve cellular mechanisms analogous to those of the late phase of
ischemic PC.
Mechanism of Augmented NOS Activity in Late PC
There are several potential mechanisms whereby brief myocardial
ischemia could elicit increased NOS activity 24 hours later.
The PC ischemia might lead to expression of iNOS in
cardiomyocytes and/or endothelial cells by
activating protein kinase C–and/or mitogen-activated protein
kinase–dependent pathways analogous to those activated by
cytokines.25 Alternatively, the PC ischemia
might elicit production of cytokines, which then would
induce iNOS expression. Ischemic PC may also induce iNOS
expression by activating nuclear factor-B, since ROS47
and NO58 (both of which are generated during
ischemia/reperfusion) are known to activate this
transcription factor, which then promotes transcription of the iNOS
gene.47 Since the expression of constitutive eNOS is known
to be modulated by a variety of factors,59,60 it is
possible that ischemia may also upregulate this enzyme.
Conclusions
Because its sustained nature offers the potential to afford
long-lasting protection, the late phase of ischemic PC may have
significant clinical implications. Accordingly, the search for the
cellular effector(s) of this phenomenon has been intense. The
present study supports the concept that the cardioprotective
effects of the late phase of ischemic PC are mediated by the
activity of NOS. Taken together with prior studies,14 the
present results indicate that NO plays a dual role in late PC
against stunning, acting initially as the trigger and subsequently as
the mediator of the protection. Regarding the source of NO, our results
with iNOS-selective inhibitors support a complex paradigm
in which two different NOS isoforms are sequentially involved in the
pathophysiological cascade of late PC, with eNOS
generating the NO that initiates the development of the PC response on
day 1 and iNOS then generating the NO that protects against recurrent
ischemia on day 2. Thus, NO formation appears to be a mechanism
of paramount importance in the adaptations of the heart to
ischemic stress.
|
Selected Abbreviations and Acronyms |
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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 and Wen-Jian Wu for expert technical assistance and Trudy Keith and Ann Keckler for expert secretarial assistance.
Received August 19, 1997; accepted September 26, 1997.
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References |
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 R. K. Kudej, Y.-T. Shen, A. P. Peppas, C.-H. Huang, W. Chen, L. Yan, D. E. Vatner, and S. F. Vatner Obligatory Role of Cardiac Nerves and {alpha}1-Adrenergic Receptors for the Second Window of Ischemic Preconditioning in Conscious Pigs Circ. Res., November 24, 2006; 99(11): 1270 - 1276. [Abstract] [Full Text] [PDF]
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 S. M. Davidson and M. R. Duchen Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance Cardiovasc Res, July 1, 2006; 71(1): 10 - 21. [Abstract] [Full Text] [PDF]
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S. Atar, Y. Ye, Y. Lin, S. Y. Freeberg, S. P. Nishi, S. Rosanio, M.-H. Huang, B. F. Uretsky, J. R. Perez-Polo, and Y. Birnbaum Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2 Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1960 - H1968. [Abstract] [Full Text] [PDF]
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X. Monnet, B. Ghaleh, L. Lucats, P. Colin, R. Zini, L. Hittinger, and A. Berdeaux Phenotypic adaptation of the late preconditioned heart: Myocardial oxygen consumption is reduced Cardiovasc Res, May 1, 2006; 70(2): 391 - 398. [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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H. Jneid, M. Chandra, M. Alshaher, C. A. Hornung, X.-L. Tang, M. Leesar, and R. Bolli Delayed Preconditioning-Mimetic Actions of Nitroglycerin in Patients Undergoing Exercise Tolerance Tests Circulation, May 24, 2005; 111(20): 2565 - 2571. [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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 Z. Xia, R. Xia, H.-T. Lan, T. Luo, Q.-Z. Tang, Z.-Y. Xia, and X.-Y. Liu Systemic ischemic preconditioning plus hemodilution enhanced early functional recovery of reperfused heart in the rabbits Interactive CardioVascular and Thoracic Surgery, September 1, 2004; 3(3): 528 - 532. [Abstract] [Full Text] [PDF]
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S. L. Lennon, J. C. Quindry, K. L. Hamilton, J. P. French, J. Hughes, J. L. Mehta, and S. K. Powers Elevated MnSOD is not required for exercise-induced cardioprotection against myocardial stunning Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H975 - H980. [Abstract] [Full Text] [PDF]
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 Y.-F. Lin, K. Raab-Graham, Y. N. Jan, and L. Y. Jan NO stimulation of ATP-sensitive potassium channels: Involvement of Ras/mitogen-activated protein kinase pathway and contribution to neuroprotection PNAS, May 18, 2004; 101(20): 7799 - 7804. [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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 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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T. C. Zhao and R. C. Kukreja Protein kinase C-{delta} mediates adenosine A3 receptor-induced delayed cardioprotection in mouse Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H434 - H441. [Abstract] [Full Text] [PDF]
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 M. M. El-Omar, R. Lord, N. J. Draper, and A. M. Shah Role of nitric oxide in posthypoxic contractile dysfunction of diabetic cardiomyopathy Eur J Heart Fail, June 1, 2003; 5(3): 229 - 239. [Abstract] [Full Text] [PDF]
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K. Laude, J. Favre, C. Thuillez, and V. Richard NO produced by endothelial NO synthase is a mediator of delayed preconditioning-induced endothelial protection Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2053 - H2060. [Abstract] [Full Text] [PDF]
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 G. Wright, J. J. Higgin, R. T. Raines, C. Steenbergen, and E. Murphy Activation of the Prolyl Hydroxylase Oxygen-sensor Results in Induction of GLUT1, Heme Oxygenase-1, and Nitric-oxide Synthase Proteins and Confers Protection from Metabolic Inhibition to Cardiomyocytes J. Biol. Chem., May 23, 2003; 278(22): 20235 - 20239. [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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 P. D. Lambiase, R. J. Edwards, M. R. Cusack, C. A. Bucknall, S. R. Redwood, and M. S. Marber Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1174 - 1182. [Abstract] [Full Text] [PDF]
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K. Shinmura, E. Kodani, Y. u-T. Xuan, B. Dawn, X.-L. Tang, and R. Bolli Effect of aspirin on late preconditioning against myocardial stunning in conscious rabbits J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1183 - 1194. [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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 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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K. Shinmura, M. Nagai, K. Tamaki, M. Tani, and R. Bolli COX-2-derived prostacyclin mediates opioid-induced late phase of preconditioning in isolated rat hearts Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2534 - H2543. [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, 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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G.F Baxter Role of adenosine in delayed preconditioning of myocardium Cardiovasc Res, August 15, 2002; 55(3): 483 - 494. [Abstract] [Full Text] [PDF]
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S. Hoshida, N. Yamashita, K. Otsu, and M. Hori The importance of manganese superoxide dismutase in delayed preconditioning: Involvement of reactive oxygen species and cytokines Cardiovasc Res, August 15, 2002; 55(3): 495 - 505. [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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K. Shinmura, R. Bolli, S.-Q. Liu, X.-L. Tang, E. Kodani, Y.-t. Xuan, S. Srivastava, and A. Bhatnagar Aldose Reductase Is an Obligatory Mediator of the Late Phase of Ischemic Preconditioning Circ. Res., August 9, 2002; 91(3): 240 - 246. [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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M. Kudo, Y. Wang, M. Xu, A. Ayub, and M. Ashraf Adenosine A1 receptor mediates late preconditioning via activation of PKC-delta signaling pathway Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H296 - H301. [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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K. Shinmura, Y.-T. Xuan, X.-L. Tang, E. Kodani, H. Han, Y. Zhu, and R. Bolli Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning Circ. Res., March 22, 2002; 90(5): 602 - 608. [Abstract] [Full Text] [PDF]
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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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E. O. McFalls, B. Murad, J.-S. Liow, M. C. Gannon, H. C. Haspel, A. Lange, D. Marx, J. Sikora, and H. B. Ward Glucose uptake and glycogen levels are increased in pig heart after repetitive ischemia Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H205 - H211. [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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L. A. Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P. Shannon Mechanisms whereby rapid RV pacing causes LV dysfunction: perfusion-contraction matching and NO Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2270 - H2281. [Abstract] [Full Text] [PDF]
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H. H. Patel and G. J. Gross Diazoxide induced cardioprotection: what comes first, KATP channels or reactive oxygen species? Cardiovasc Res, September 1, 2001; 51(4): 633 - 636. [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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 N. Blondeau, C. Widmann, M. Lazdunski, and C. Heurteaux Activation of the Nuclear Factor-{kappa}B Is a Key Event in Brain Tolerance J. Neurosci., July 1, 2001; 21(13): 4668 - 4677. [Abstract] [Full Text] [PDF]
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R. A. Ockaili, P. Bhargava, and R. C. Kukreja Chemical preconditioning with 3-nitropropionic acid in hearts: role of mitochondrial KATP channel Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2406 - H2411. [Abstract] [Full Text] [PDF]
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 B. P. Lipton, J. B. Delcarpio, and K. H. McDonough Effects of Endotoxin on Neutrophil-Mediated Ischemia/Reperfusion Injury in the Rat Heart In Vivo Experimental Biology and Medicine, April 1, 2001; 226(4): 320 - 327. [Abstract] [Full Text]
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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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O. Parent De Curzon, B. Ghaleh, R. Tissier, J.-F. Giudicelli, L. Hittinger, and A. Berdeaux Myocardial stunning in exercise-induced ischemia in dogs: lack of late preconditioning Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H302 - H310. [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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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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 T. J. Koh and J. G. Tidball Nitric oxide inhibits calpain-mediated proteolysis of talin in skeletal muscle cells Am J Physiol Cell Physiol, September 1, 2000; 279(3): C806 - C812. [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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 G. L. Semenza HIF-1 and human disease: one highly involved factor Genes & Dev., August 15, 2000; 14(16): 1983 - 1991. [Full Text]
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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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G. Valen, G. K Hansson, A. Dumitrescu, and J. Vaage Unstable angina activates myocardial heat shock protein 72, endothelial nitric oxide synthase, and transcription factors NF{kappa}B and AP-1 Cardiovasc Res, July 1, 2000; 47(1): 49 - 56. [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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T. Oxman, M. Shapira, A. Diver, R. Klein, N. Avazov, and B. Rabinowitz A new method of long-term preventive cardioprotection using Lactobacillus Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1717 - H1724. [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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M. Barton Sex and NO -- beyond regulation of vasomotor tone Cardiovasc Res, April 1, 2000; 46(1): 20 - 23. [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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A. J. Spanier and K. H. McDonough Dexamethasone Blocks Sepsis-Induced Protection of the Heart from Ischemia Reperfusion Injury Experimental Biology and Medicine, January 1, 2000; 223(1): 82 - 87. [Abstract] [Full Text]
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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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R. Ockaili, V. R. Emani, S. Okubo, M. Brown, K. Krottapalli, and R. C. Kukreja Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2425 - H2434. [Abstract] [Full Text] [PDF]
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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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C. Csonka, Z. Szilvassy, F. Fulop, T. Pali, I. E. Blasig, A. Tosaki, R. Schulz, and P. Ferdinandy Classic Preconditioning Decreases the Harmful Accumulation of Nitric Oxide During Ischemia and Reperfusion in Rat Hearts Circulation, November 30, 1999; 100(22): 2260 - 2266. [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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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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Y.-T. Xuan, X.-L. Tang, S. Banerjee, H. Takano, R. C. X. Li, H. Han, Y. Qiu, J.-J. Li, and R. Bolli Nuclear Factor-{kappa}B Plays an Essential Role in the Late Phase of Ischemic Preconditioning in Conscious Rabbits Circ. Res., May 14, 1999; 84(9): 1095 - 1109. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, X. Cao, R. C. X. Li, D. Kong, X.-L. Tang, Y. Qiu, S. Manchikalapudi, J. A. Auchampach, R. G. Black, et al. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1468 - H1481. [Abstract] [Full Text] [PDF]
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P. Ping, H. Takano, J. Zhang, X.-L. Tang, Y. Qiu, R. C. X. Li, S. Banerjee, B. Dawn, Z. Balafonova, and R. Bolli Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits : A Signaling Mechanism for Both Nitric Oxide–Induced and Ischemia-Induced Preconditioning Circ. Res., March 19, 1999; 84(5): 587 - 604. [Abstract] [Full Text] [PDF]
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Q. Li, R. Bolli, Y. Qiu, X.-L. Tang, S. S. Murphree, and B. A. French Gene Therapy With Extracellular Superoxide Dismutase Attenuates Myocardial Stunning in Conscious Rabbits Circulation, October 6, 1998; 98(14): 1438 - 1448. [Abstract] [Full Text] [PDF]
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Y. Guo, W.-J. Wu, Y. Qiu, X.-L. Tang, Z. Yang, and R. Bolli Demonstration of an early and a late phase of ischemic preconditioning in mice Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1375 - H1387. [Abstract] [Full Text] [PDF]
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H. Takano, S. Manchikalapudi, X.-L. Tang, Y. Qiu, A. Rizvi, A. K. Jadoon, Q. Zhang, and R. Bolli Nitric Oxide Synthase Is the Mediator of Late Preconditioning Against Myocardial Infarction in Conscious Rabbits Circulation, August 4, 1998; 98(5): 441 - 449. [Abstract] [Full Text] [PDF]
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H. Takano, X.-L. Tang, Y. Qiu, Y. Guo, B. A. French, and R. Bolli Nitric Oxide Donors Induce Late Preconditioning Against Myocardial Stunning and Infarction in Conscious Rabbits via an Antioxidant-Sensitive Mechanism Circ. Res., July 13, 1998; 83(1): 73 - 84. [Abstract] [Full Text] [PDF]
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S. Pudupakkam, K. A. Harris, W. G. Jamieson, G. DeRose, J. A. Scott, M. W. Carson, M. G. Schlag, P. R. Kvietys, and R. F. Potter Ischemic tolerance in skeletal muscle: role of nitric oxide Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H94 - H99. [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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K. Shinmura, Y.-T. Xuan, X.-L. Tang, E. Kodani, H. Han, Y. Zhu, and R. Bolli Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning Circ. Res., March 22, 2002; 90(5): 602 - 608. [Abstract] [Full Text] [PDF]
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