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Experimental Research Laboratory, Division of Cardiology, University of Louisville and Jewish Hospital Heart and Lung Institute, Louisville, Kentucky 40292
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although
previous studies suggested that the protection of late preconditioning
(PC) against myocardial stunning is mediated by nitric oxide (NO),
direct evidence that exogenous administration of NO attenuates
myocardial stunning is lacking. Furthermore, although exogenous
NO administration was shown to elicit a late PC phase, it is unknown
whether NO donors also induce an early PC phase. Therefore, conscious
rabbits underwent two experimental stages (3 days of six 4-min
occlusion/4-min reperfusion cycles each) 2 wk apart. In
study
I, both stages were control stages (n = 7). In
studies
II and
III,
stage
I was the control stage. On
day 1 of stage
II, seven rabbits received infusion of
nitroglycerin (NTG; 2 µg · kg
1 · min1
iv) during the ischemia-reperfusion sequence, starting 30 min before the 1st occlusion and ending 10 min after the 6th reperfusion (study
II). Another seven rabbits received
infusion of NTG (2 µg · kg1 · min1
iv) for 1 h followed by a 30-min washout interval and then underwent six 4-min occlusion/4-min reperfusion cycles
(study
III). In the control stage of all
three studies, recovery of wall thickening (WTh) after
occlusion/reperfusion cycles was markedly enhanced on
days
2 and
3 compared with
day
1, indicating late PC. In
study II, infusion of NTG during the
occlusion/reperfusion cycles on day
1 resulted in significant and
sustained enhancement in WTh recovery. A similar attenuation of
stunning was observed in study IV in six rabbits given intravenous
infusion of
S-nitroso-N-acetylpenicillamine (SNAP) during occlusion/reperfusion cycles. The magnitude of the protection afforded by NTG and SNAP was comparable to that afforded by
the late ischemic PC phase. In contrast, in
study
III infusion of NTG before
occlusion/reperfusion cycles did not enhance WTh recovery, indicating
that NTG failed to induce an early PC effect against stunning. This
study demonstrates that administration of hemodynamically inactive
doses of two unrelated NO donors alleviates myocardial stunning in
conscious rabbits, providing direct evidence for a protective action of
NO in this setting.
myocardial ischemia; reperfusion injury; left ventricular function; nitroglycerin
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE DEVELOPMENT OF POWERFUL protection against myocardial stunning is one of the most consistent aspects of the late phase of ischemic preconditioning (PC) (4, 8). Our laboratory reported (5-7, 21, 31-33, 35-37, 39, 45) that PC with repetitive cycles of brief ischemia induces robust protection against myocardial stunning 24-72 h later in conscious pigs and rabbits. In recent years, a number of pharmacological studies have indicated that the production of nitric oxide (NO) is both the trigger and the mediator of late PC against stunning (Refs. 5, 7; reviewed in Ref. 6). However, direct evidence that NO attenuates myocardial stunning is still lacking. If increased biosynthesis of NO by NO synthase is responsible for the protective effects of late PC, then exogenous administration of NO donors should reproduce the protection of late PC against myocardial stunning. At present, the ability of NO precursors (such as L-arginine) or NO-releasing agents to mitigate the severity of postischemic myocardial stunning in vivo remains controversial. Infusion of L-arginine has been reported to aggravate myocardial stunning in open-chest dogs (26). Nitroglycerin (NTG) has been found to alleviate myocardial stunning in open-chest rabbits, but the duration of the reperfusion interval (30 min) was too short to enable definitive conclusions (17). In an earlier study in open-chest dogs, Gross et al. (13) found that NTG enhanced the recovery of segmental shortening only transiently (in the first 30 min of reperfusion) and that regional myocardial function was indistinguishable between control and treated animals by 2 h of reperfusion. Thus evidence that NO donors can effect a sustained mitigation of myocardial stunning is still lacking.
In addition, although exogenous NO administration was shown to elicit a late phase of protection equivalent to the late phase of ischemic PC (37), it is unknown whether NO donors also induce an early phase of PC. We have found that intravenous administration of NTG mimics late PC against stunning 24 h later via a protein kinase C (PKC)-dependent pathway (3). The activation of PKC is also known to be a key step in the development of the early phase of PC (20, 46). However, it is unknown whether the same dosage of NTG that elicits a late PC effect against stunning 24 h later can also produce an early PC effect against stunning.
Thus there were two aims in this study. First, we sought to determine whether infusion of two unrelated NO donors [NTG and S-nitroso-N-acetylpenicillamine (SNAP)] during ischemia-reperfusion attenuates myocardial stunning in conscious rabbits. Second, we investigated whether pretreatment with the same dosage of NTG that was previously shown to induce a late PC effect (3) can also induce an early PC effect against myocardial stunning in conscious rabbits.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The conscious rabbit model of myocardial ischemia was described in detail previously (5, 7, 21, 31, 32, 37, 45) and is briefly summarized here.
Experimental Preparation
New Zealand White male rabbits (wt 2.4 ± 0.1 kg) were instrumented under sterile conditions with a balloon occluder around a major branch of the left coronary artery, a 10-MHz pulsed Doppler ultrasonic crystal in the center of the region to be rendered ischemic, and bipolar electrocardiogram (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 14 days after surgery.Experimental Protocols
Throughout the experiments, rabbits were kept in a cage in a quiet room. Left ventricular (LV) systolic wall thickening (WTh), range gate depth, and the ECG were continuously recorded on a thermal array chart recorder. Regional myocardial function was assessed as systolic thickening fraction using the pulsed Doppler probe, as previously described (9). No sedative or antiarrhythmic agents were given on any day. A total of 33 rabbits were assigned to four studies (Fig. 1).
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Study I (control study).
In this study, as well as in studies
II and
III, all rabbits underwent two stages
of experiments, each consisting of three consecutive days of six 4-min
coronary occlusion/4-min reperfusion cycles. The performance of
successful coronary occlusion was verified by observing the development
of S-T segment elevation and changes in the QRS complex on the ECG and
the appearance of paradoxical wall thinning on the ultrasonic crystal
recordings. In stage
I (control stage), rabbits underwent
three consecutive days of six 4-min coronary occlusion/4-min
reperfusion cycles without any treatment. Two weeks later, they again
underwent three consecutive days of six 4-min coronary occlusion/4-min
reperfusion cycles. On day
1 of
stage
II, rabbits received an intravenous
infusion of saline (20 µl · kg1 · min1),
starting 30 min before the first occlusion and ending 10 min after the
sixth reperfusion (Fig. 1).
Study II (NTG treatment).
In stage
I (control stage), rabbits underwent
three consecutive days of six 4-min coronary occlusion/4-min
reperfusion cycles without any treatment. Two weeks later, they again
underwent three consecutive days of six 4-min coronary occlusion/4-min
reperfusion cycles. On day
1 of
stage
II, rabbits received an intravenous infusion of NTG (2 µg · kg1 · min1),
starting 30 min before the first occlusion and ending 10 min after the
sixth reperfusion (Fig. 1). NTG was diluted in normal saline and
infused at a rate of 20 µl · kg1 · min1
for 84 min. This rate of NTG infusion was selected because it is
effective in inducing late PC against myocardial stunning in conscious
rabbits (3) and also because it was found in pilot studies to be the
highest dosage that could be given to conscious rabbits without causing
hemodynamic changes.
Study III (NTG pretreatment).
In stage
I (control stage), rabbits underwent
three consecutive days of six 4-min coronary occlusion/4-min
reperfusion cycles without any treatment. Two weeks later, they again
underwent three consecutive days of six 4-min coronary occlusion/4-min
reperfusion cycles. On day
1 of
stage
II, rabbits received an intravenous infusion of NTG (2 µg · kg1 · min1)
for 1 h followed by a 30-min washout interval and then underwent six
4-min occlusion/4-min reperfusion cycles (Fig. 1). NTG was diluted in
normal saline; the total volume of the solution that was administered
over 60 min was 1.68 ml/kg. This rate and duration of NTG infusion were
selected because they have previously been shown to induce late PC
against myocardial stunning 24 h later in conscious rabbits (3),
thereby making it possible to directly compare the early and late PC
effects of NTG.
Study IV (SNAP treatment).
Rabbits were subjected to six 4-min occlusion/4-min reperfusion cycles
and received an intravenous infusion of SNAP (2.5 µg · kg1 · min1),
starting 30 min before the first occlusion and ending 10 min after the
sixth reperfusion (Fig. 1). This rate of SNAP infusion was selected
because it is effective in inducing late PC against myocardial stunning
in conscious rabbits (37).
Measurement of Regional Myocardial Function
Regional myocardial function was assessed as systolic thickening fraction using a Doppler probe, as previously described (9). Systolic thickening fraction was calculated as the ratio of net systolic WTh to end-diastolic wall thickness, multiplied by 100 (9). The total deficit of systolic WTh after the sixth reperfusion (an integrative assessment of the overall severity of postischemic dysfunction) was calculated as the area between the systolic WTh-versus-time line and the baseline (100% line) during the 5-h recovery period (5, 7, 21, 31, 32, 37, 45). In all animals, measurements from at least 10 beats were averaged at baseline and from at least 5 beats at all subsequent time points.Statistical Analysis
Data are reported as means ± SE. For intragroup comparisons, hemodynamic variables and WTh were analyzed by a two-way repeated-measures ANOVA (time and group), followed by Student's t-tests for paired data with the Bonferroni correction. For intergroup comparisons, data were analyzed by either a one-way or a two-way repeated-measures ANOVA (time and group), as appropriate, followed by Student's t-tests for paired data with the Bonferroni correction. All statistical analyses were performed using the SAS software system.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamic Parameters
In four rabbits, arterial blood pressure was measured using a 22-gauge angiocatheter inserted into the middorsal ear artery as previously described (5). Infusion of 2 µg · kg1 · min1
of NTG for 1 h did not produce significant changes in mean arterial blood pressure, consistent with previous reports from our laboratory (85 ± 5 mmHg at baseline, 84 ± 6 mmHg at 30 min into the
infusion, and 80 ± 6 mmHg at end of the infusion; Ref. 3).
Exclusions
Of the 33 rabbits instrumented for the studies of myocardial stunning, 5 were excluded because the WTh signal was lost before the protocol was completed (1 in study I, 2 in study II, and 2 in study III). One rabbit in study III died of ventricular fibrillation during the fifth occlusion on day 3 of stage II. Thus seven rabbits completed the protocol in study I, seven in study II, seven in study III, and six in study IV.Study I (control study).
As expected (5, 7, 21, 32, 45), in both
stages
I and
II the recovery of WTh during the 5-h
reperfusion period was significantly improved on
days
2 and
3 compared with
day
1, resulting in a marked decrease in
the total deficit of WTh versus day
1 (Fig. 2;
late PC against stunning). There was no difference in thickening
fraction between stage
I and
stage
II of
day 1 (Fig. 3), between
stage
I and
stage
II of
day 2 (data not shown), or between stage
I and
stage
II of day 3 (data not shown).
Similarly, the total deficit of WTh on corresponding days was similar
between stage
I and
stage
II (Fig. 2). These results demonstrate
that the severity of myocardial stunning on two subsequent stages 2 wk
apart is reproducible in this model and that neither the 2-wk interval
nor the infusion of saline had any appreciable effect on the degree of
myocardial stunning.
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Study II (NTG treatment).
There were no appreciable differences in heart rate throughout the
experimental protocol among stage
I of
days
1, 2,
and 3 and
stage
II of
days
1, 2,
and 3 (Table
1). In addition, there were no differences
in thickening fraction at baseline and just before coronary occlusion
(Table 2).
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Study III (NTG pretreatment). There were no appreciable differences in heart rate throughout the experimental protocol among stage I of days 1, 2, and 3 and stage II of days 1, 2, and 3 (Table 1). In addition, there were no differences in thickening fraction at baseline and just before coronary occlusion (Table 2).
The results of stage I (control stage) were similar to those obtained in studies I and II (Fig. 7). On day 1 of stage II (NTG pretreatment stage), infusion of NTG before the six occlusion/reperfusion cycles failed to enhance the recovery of WTh (except for a transient improvement at 15 and 30 min; Fig. 8) or to attenuate the total deficit of WTh (Fig. 7). On days 2 and 3 of stage II, the recovery of WTh (data not shown) and the total deficit of WTh (Fig. 7) exhibited changes similar to those noted in the absence of any treatment (study I).
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Study IV (SNAP treatment).
Heart rate (Table 1) and thickening fraction at baseline and before
occlusion (Table 2) were similar in SNAP-treated rabbits and in control
rabbits (study
I,
day 1 of stage
II). In four rabbits in which
arterial pressure was measured, infusion of SNAP before and during the
six 4-min occlusion/reperfusion cycles had no appreciable effect (mean
arterial pressure: 81 ± 4 mmHg at baseline, 78 ± 3 mmHg during
1st occlusion, 78 ± 2 mmHg during 6th occlusion, and 81 ± 4 mmHg at 30 min after 6th occlusion). Compared with control rabbits,
infusion of SNAP effected a significant enhancement in the recovery of
WTh, which became evident immediately after the sixth reperfusion and
persisted for 4 h thereafter (Fig. 9). Accordingly, the deficit of WTh was reduced by 40% in SNAP-treated rabbits compared with control rabbits (Fig. 9).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that infusion of hemodynamically inactive doses of two unrelated NO donors, NTG and SNAP, results in a significant and sustained attenuation of myocardial stunning. To our knowledge, this is the first report that exogenous administration of NO mitigates myocardial stunning in vivo.
Despite extensive investigation, the influence of NO on myocardial
ischemia-reperfusion injury remains controversial. Although a
number of studies support the notion that endogenous production of NO
is cardioprotective (12, 14, 15, 27, 42, 43), others have arrived at
opposite conclusions (28, 30, 38, 44). The effect of NTG on myocardial
ischemia-reperfusion injury is also controversial. For example,
a nonhypotensive dose of NTG reduced infarct size in dogs (24, 25) but
this beneficial effect was not observed in open-chest rabbits (16) or
pigs (18). The reasons for these discrepant results remain unclear.
With regard to myocardial stunning, most of these studies have examined models in which ischemia caused at least some degree of cell
death, thereby making it difficult to formulate conclusions regarding the influence of NO on myocardial stunning per se. Only a few reports
specifically examined the effect of NO on this latter manifestation of
ischemia-reperfusion injury. Hasebe et al. (14) showed that
administration of
N
-nitro-L-arginine in conscious
dogs subjected to a 10-min coronary occlusion aggravates myocardial
stunning independent of any effects on regional perfusion, supporting
the notion that NO functions as an endogenous protectant against
postischemic dysfunction. On the other hand, Mori et al. (26)
reported that intracoronary administration of
L-arginine just before
reperfusion exacerbated myocardial stunning after a 15-min coronary
occlusion in dogs. These authors concluded that NO plays a detrimental
role in myocardial stunning through the formation of peroxynitrite.
Ehring et al. (11), however, observed no improvement in the recovery of
WTh when open-chest dogs subjected to a 15-min coronary occlusion were
pretreated with NG-nitro-L-arginine
methyl ester. Iwamoto et al. (17) found in open-chest rabbits that
administration of NTG throughout a 10-min coronary occlusion and
subsequent reperfusion resulted in increased recovery of thickening
fraction. However, because the thickening fraction was followed for
only 30 min, it was not possible to determine whether this beneficial
effect of NTG was sustained for the entire duration of stunning.
Furthermore, NTG was infused throughout the reperfusion phase, so that
it is not possible to establish whether the enhanced recovery was
dependent on continuous supply of the drug. In a study in open-chest
dogs, Gross et al. (13) found that infusion of NTG for 30 min before a
15-min coronary occlusion resulted in only an ephemeral augmentation of
segment shortening at 5 and 15 min of reperfusion and that there were no subsequent significant differences between control and treated dogs.
Because of the numerous differences among these studies (13, 16-18, 24, 25), including species, presence or absence of anesthesia, and dose and duration of NTG infusion, it is not possible to identify the reason(s) for the apparently discrepant results. It is conceivable that the protective effects of NTG on myocardial stunning may be demonstrable only in the conscious state, because the conditions associated with open-chest preparations produce an approximately twofold increase in the severity of myocardial stunning (40). This supposition is reinforced by the finding of Hasebe et al. (14) that blockade of endogenous NO synthesis exacerbates myocardial stunning in conscious dogs. In contrast to the finding of Mori et al. (26), Engelman et al. (12) reported that pretreatment with L-arginine improved the recovery of LV function in open-chest pigs subjected to 30 min of regional ischemia followed by 90 min of reperfusion. Although this finding demonstrates a protective effect of enhanced NO biosynthesis, the duration of coronary occlusion (30 min) was associated with some degree of infarction, making it difficult to distinguish between a reduction in infarct size and an improvement in myocardial stunning per se.
The rationale for testing two different NO donors in this study was to
minimize the likelihood that the protective effects observed could be
caused by nonspecific actions. The choice of NTG as one of the NO
donors to be tested was dictated by the preclinical nature of this
investigation. NTG, a widely used nitrate, has been employed for the
treatment of coronary artery disease for over 100 years. Accordingly,
we reasoned that demonstrating a protective effect of NTG against
myocardial stunning would have relevance for the treatment of patients
with transient myocardial ischemia and subsequent postischemic
dysfunction. The dosage of NTG used in
study
III (NTG pretreatment; 2 µg · kg1 · min1
for 60 min) was chosen because it was shown previously to induce late
PC against myocardial stunning in this same conscious rabbit model (3),
thereby making it possible for us to directly compare the early and
late PC effects of NTG. Although it is theoretically possible that a
different dosage might be effective in eliciting early PC, infusion
rates of NTG >2
µg · kg1 · min1
resulted in significant decreases in arterial pressure in our pilot
studies. In study
II (NTG treatment), we used the same
infusion rate (2 µg · kg1 · min1)
but extended the duration of infusion to 84 min to bracket the entire
six occlusion/reperfusion cycles as well as the 30 min preceding the
first occlusion and the 10 min after the sixth reperfusion. The
rationale for this was to ensure that steady-state NTG plasma levels
were present at the beginning of the occlusion/reperfusion cycles and
in the initial minutes of reperfusion.
The precise mechanism whereby NO attenuates myocardial stunning remains
to be elucidated. NO exerts a number of actions that would be expected
to be beneficial during ischemia-reperfusion, including
inhibition of the influx of Ca2+
into myocytes (19, 22), antagonism of 
-adrenergic stimulation (2,
41), and opening of ATP-sensitive
K+ channels (1, 34).
Interestingly, the magnitude of the beneficial effects on myocardial
stunning of both NTG treatment and SNAP treatment was comparable to
that observed during the late phase of ischemic PC, as demonstrated by
the fact that in study
II there were no significant
differences in the deficit of WTh between stage
I of
day 2 and stage
II of
day 1 (Fig. 4) and that the deficit of WTh in
day 1 of study
IV (Fig. 9) was similar to that
observed on day
2 of
stage
II in
study
I (Fig. 2). Thus the beneficial effects of the late phase of ischemic PC could be reproduced by administration of exogenous NO, further supporting the hypothesis that
NO mediates this cardioprotective phenomenon.
A report by Banerjee et al. (3) showed that the same dosage of NTG used in this investigation elicits late PC against myocardial stunning 24 h later in conscious rabbits and that this effect is blocked by chelerythrine, indicating that it is mediated by PKC-dependent signaling. The failure of NTG to induce early PC in the present study suggests that PKC activation, although essential for the late PC effect of NTG, is not sufficient to induce an early protective effect against myocardial stunning. In this connection, it is important to point out that although the early phase of ischemic PC is remarkably powerful in protecting against cell death, its effects on stunning are controversial (4). Studies using a single 15-min period of coronary occlusion failed to demonstrate an early PC effect against stunning (4, 23, 29). On the other hand, when the heart is subjected to a sequence of brief coronary occlusion/reperfusion cycles, the first cycle has been found to precondition against the stunning induced by the next two cycles (10).
In conclusion, we have demonstrated that intravenous infusion of NTG or SNAP during brief ischemia-reperfusion is effective in attenuating myocardial stunning and that the magnitude of this protection is comparable to that induced by the late phase of ischemic PC. These results have obvious clinical implications for the use of NO donors in the treatment of patients with coronary artery disease. In addition, they provide direct evidence for a protective action of NO in the setting of myocardial stunning.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge Gregg Shirk and Larisa Hodge for expert technical assistance and Trudy Keith for expert secretarial assistance.
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FOOTNOTES |
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This study was supported in part by National Heart, Lung, and Blood Institute Grants R01 HL-43151 and HL-55757 (R. Bolli), by an American Heart Association, Kentucky Affiliate Grant, by American Heart Association, Ohio Valley Affiliate Grant 9951533V (X.-L. Tang), and by the Medical Research Grant Program of the Jewish Hospital Foundation, Louisville, KY.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. Bolli, Div. of Cardiology, Univ. of Louisville, Louisville, KY 40292 (E-mail: rbolli{at}louisville.edu).
Received 30 July 1999; accepted in final form 24 August 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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