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1 Henry Hood Research Program, Weis Center for Research, Pennsylvania State University College of Medicine, Danville 17822; Department of Cellular and Molecular Physiology and 2 Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and 3 Merck Research Laboratories, West Point, Pennsylvania 19486
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined whether nitric oxide (NO)
inhibition during moderate reduction in coronary blood flow (CBF) would
affect perfusion-contraction matching. Coronary stenosis (CS) was
induced in conscious pigs, which resulted in a stable 39 ± 1%
reduction in CBF for 1.5 h. Ischemic zone wall thickening (IZWT)
decreased by an average of 56 ± 2% during CS from 2.7 ± 0.2 mm. After reperfusion, myocardial stunning was observed, but this
recovered without evidence of necrosis. After recovery and subsequent
administration of systemic NO synthase inhibition
(N
-nitro-L-arginine, 25 mg
· kg
1 · day1 × 3 days), CS
for 1.5 h reduced CBF similarly but decreased IZWT significantly
more, P < 0.05, by 89 ± 5%. Myocardial
stunning, i.e., the decrease in IZWT at 12 h post-CS, was more
severe (
65 ± 5% vs. 21 ± 3%), P < 0.05. Furthermore, CS during NO synthase inhibition resulted in
multifocal subendocardial areas of necrosis in the area at risk. These
data suggest that in the intact, conscious pig, NO inhibition prevents
perfusion-contraction matching, resulting in intensification of
post-ischemic stunning and development of subendocardial necrosis.
myocardium; ischemia; infarction; stunning
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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DURING
CORONARY STENOSIS (CS) of brief duration, e.g., 90 min, the
reduced blood flow is thought to induce downregulation of function such
that there is perfusion-contraction matching (22), also
termed short-term hibernation (11, 23). This is thought to protect the heart so that myocardial necrosis does not
result. The mechanism of perfusion-contraction matching is unknown. Our
hypothesis was that nitric oxide (NO) might mediate this
perfusion-contraction matching, and, accordingly, after inhibition of
NO synthase, the 90-min period of CS would no longer be completely reversible. To test this hypothesis, we examined the effects of a
90-min period of CS in the absence and then, several days later, in the
presence of NO synthase inhibition
(N-nitro-L-arginine,
L-NNA). We examined whether the NO synthase inhibition
altered the flow-function relationship and perfusion-contraction matching, resulting in intensified postreperfusion myocardial stunning
or in subendocardial necrosis.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Nineteen domestic swine, weighing 23.2 ± 0.9 kg, were sedated with telazol (5 mg/kg im) and atropine (0.05 mg/kg im). General anesthesia was maintained with isoflurane (0.5-1.5 vol%) following tracheal intubation. The animals were trained and instrumented with the use of sterile surgical technique, and hemodynamic recordings were made as previously described (15). Animals used in this study were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, Revised 1996).
Twelve pigs were used for the protocol involving two periods of 1.5-h
CS, i.e., before and during NO synthase inhibition. Three pigs were
used for the two periods of 1.5-h CS protocol, each without NO synthase
inhibition. Two pigs were used for a single 1.5-h CS protocol without
NO synthase inhibition. Two pigs were used for a single 1.5-h CS
protocol during NO synthase inhibition. Valium was administered at
0.5-1.0 mg/kg for tranquilization before initiation of the
experimental protocol and additionally as required, i.e., if the pigs
became agitated transiently. After baseline hemodynamic data were
recorded, CS was induced and continuously monitored to reduce coronary
blood flow by ~40% for 1.5 h. After a 4-day recovery period,
systemic NO synthase inhibition (L-NNA, 25 mg · kg1 · day1 × 3 days) was
initiated, and a second 1.5-h CS was induced to match the coronary
blood flow reduction induced during the first CS. Blood samples
(coronary sinus and arterial) were taken from three animals before and
during CS, in the absence and presence of L-NNA, to assess
myocardial oxygen consumption. After an additional 4 days, the animals
were killed with an acute overdose of pentobarbital sodium, and
the hearts were removed.
Regional myocardial blood flow measurements, using the radioactive
microsphere technique, and calculation of the area at risk and
frequency distribution of blood flow within the area at risk were
performed as previously described (15). Radioactive
microspheres were administered at baseline and twice (30 and 90 min)
during each CS. Five of the pigs that were studied both before and
during NO synthase inhibition had the entire area at risk analyzed for frequency distribution of blood flow. Each heart was sectioned into an
average of 336 ± 13 pieces with each piece weighing an average of
0.23 ± 0.01 g. The frequency distribution of blood flows was
analyzed for each animal by grouping tissue flow samples from all
149 ± 10 pieces within the area at risk at each 0.1 ml · min1 · g1 and summing the frequency
of occurrence in each group.
Evaluation of ischemic necrosis. Before the tissue was divided for blood flow determination, histology samples were taken from 11 of 19 pigs. A total of 5-10 transmural samples were taken from 2 or 3 left ventricle (LV) slices within the area at risk, and additional samples were taken from the nonischemic regions. The tissue samples were embedded in paraffin, sectioned, and stained with hematoxylin and eosin and Gomori aldehyde fuchsin trichrome. The stained sections of the heart were observed under a light microscope equipped with a video camera that was connected to a computer workstation. Subendo-, midmyo-, and subepicardial layers were defined by dividing the transmural wall into equal thirds, independent of the papillary muscle. The images from the subendocardial region of the heart were recorded, digitized, and printed in color. The areas of normal and patchy necrotic zones were evaluated using an overlying grid and point-counting system. Lesions that resulted from the second period of CS were characterized by early healing necrosis, whereas the lesions from the first period of CS were characterized by early replacement fibrosis.
Data/statistics. All data are reported as means ± SE. Paired data were examined statistically for all comparisons. Myocardial functional and coronary blood flow data were recorded continuously before, during, and for 3 h after CS but were analyzed at 5, 30, 60, and 90 min during CS. These values were averaged and reported as average CS in the tables. Hemodynamics and regional myocardial blood flows during CS and reperfusion were analyzed using a repeated measures ANOVA. If the ANOVA indicated statistical significance, the average value during CS was compared using a Student's t-test for paired comparison with P < 0.05 taken as the level for significance. The average percent necrosis of the subendocardium was compared using a Student's t-test for unpaired comparison with P < 0.05 taken as the level for significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of CS.
Changes in coronary blood flow and ischemic zone wall thickening during
1.5 h of CS and at 12 h and 4 days of reperfusion are
represented in Fig. 1. Hemodynamic and
regional function measurements at baseline and during CS and recovery
values at 12 h and 4 days after coronary artery reperfusion are
listed in Table 1. Coronary blood flow
was reduced by an average of 39 ± 1% during the control CS from
a baseline of 31 ± 3 ml/min, and ischemic zone wall thickening decreased similarly by an average of 45 ± 3% from 2.7 ± 0.2 mm immediately after CS. However, ischemic zone wall thickening
continued to decrease, i.e., was reduced by 61 ± 3% from
baseline at the end of the 1.5 h of CS. After 12 h of
reperfusion, coronary blood flow had returned to baseline levels, but
ischemic zone wall thickening remained depressed (P < 0.05) by 21 ± 3% from baseline. At 4 days after CS, ischemic
zone wall thickening had returned to baseline. There were moderate but
significant changes in LV end-diastolic pressure and the rate of change
in LV pressure (dP/dt) during CS (noted in Table 1),
whereas other hemodynamic variables did not change significantly with
CS.
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Effects of NO synthase inhibition.
After three days of L-NNA (25 mg · kg1 · day1), LV systolic pressure
had increased by an average of 29 ± 2% (P < 0.05) to 148 ± 4 mmHg, and baseline heart rate had decreased from
an average of 118 ± 4 to 109 ± 4 beats/min
(P < 0.05). Coronary blood flow (33 ± 3 ml/min)
and LV dP/dt (2,483 ± 114 mmHg/s) remained unchanged from control values (Table 1). Myocardial oxygen consumption was
measured in three animals in the absence and presence of NO synthase
inhibition. Myocardial oxygen consumption at baseline (3.43 ± 0.22 ml/min) was unchanged after NO synthase inhibition (3.44 ± 0.26 ml/min). In addition, myocardial oxygen
consumption was similar during CS in the absence (2.27 ± 0.10 ml/min) and in the presence (2.27 ± 0.11 ml/min) of NO synthase inhibition.
Effects of CS with systemic NO synthase inhibition.
Changes in coronary blood flow and ischemic zone wall thickening during
1.5 h of CS with systemic NO synthase inhibition and at 12 h
and 4 days of reperfusion are also represented in Fig. 1, along with
similar values for CS before systemic NO synthase inhibition.
Hemodynamic and regional function measurements at baseline and during
CS and recovery values at 12 h and 4 days after coronary artery
reperfusion are listed in Table 1. Although coronary blood flow was
reduced with the CS during systemic NO synthase inhibition (37 ± 2%), similar to the control CS (39 ± 1%) because of the
experimental design, ischemic zone wall thickening decreased
significantly more (P < 0.05) at 5 min after CS
(87 ± 5%) and did not decline further during the 1.5 h of
CS. After 12 h of reperfusion, coronary blood flow was similar to
baseline, but post-CS regional wall thickening was more severely
depressed (P < 0.05), i.e., ischemic zone wall
thickening was still reduced by 65 ± 5% compared with the
control response (21 ± 3%) in the absence of
L-NNA. Ischemic zone wall thickening even remained depressed by 38 ± 9% from baseline after 4 days of reperfusion.
Myocardial blood flow distribution within the area at risk.
Absolute values for tissue blood flows (ml · min1 · g1) in the ischemic zone,
both for control and during systemic NO synthase inhibition, are listed
in Table 2. During CS, transmural tissue blood flows decreased similarly to decreases observed with flowmeter measurement. However, subepicardial blood flow did not decrease significantly with CS either in the absence or presence of NO synthase
inhibition, whereas subendocardial blood flow decreased by 61 ± 6 and 57 ± 8%, respectively.
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Frequency distribution of blood flow during CS. Frequency distribution analysis was performed in five pigs studied before and after NO synthase inhibition. This analysis showed a clear redistribution of blood flow during the CS in the subendocardium but not in the subepicardium. Both subendocardial and midmyocardial flow during CS demonstrated a significant shift to the left in both the absence and presence of NO synthase inhibition. However, distribution of subepicardial flow during CS demonstrated no significant change from baseline in either the absence or presence of systemic NO synthase inhibition. Importantly, NO synthase inhibition did not alter the frequency distribution of blood flow either before or during CS.
Evaluation of tissue necrosis.
Histology was assessed in four of the five animals that had either one
or two 1.5-h periods of CS without L-NNA and showed little
evidence of necrosis. All four pigs studied without
L-NNA demonstrated trivial patchy necrosis averaging
0.6 ± 0.6% of the subendocardium. However, in the two animals
that underwent a single 1.5 h of CS in the presence of
L-NNA and in the five pigs assessed with two 1.5-h periods
of CS in the absence and in the presence of L-NNA, the
amount of necrosis in the subendocardium (Fig.
2) averaged 27.8 ± 6.6% of the
subendocardium due to the CS in the presence of L-NNA.
These data were different (P < 0.05) from data observed in pigs without L-NNA treatment. The subepicardium
was spared in both groups of pigs. The midmyocardium demonstrated no
evidence of patchy necrosis in pigs with CS in the absence of
L-NNA, but there was 12.0 ± 4.3% patchy necrosis in
the pigs with CS pretreated with L-NNA.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The role of NO during myocardial ischemia and reperfusion remains controversial, probably because of its multifaceted actions. It is therefore conceivable that individual mechanisms elucidated in cultured cells or even in isolated hearts might differ from the integrative action in the intact animal or patient with myocardial ischemia. Indeed, the majority of studies demonstrating a deleterious effect of NO during ischemia and reperfusion have been conducted in isolated hearts (6, 7, 18, 24, 28-31). Conversely, the majority of studies demonstrating a protective effect of NO have been conducted in vivo in intact conscious animals (10) or in animals with an open chest (5, 12, 16, 19, 20). These prior studies used as an end point either the effects of NO on ischemia or reperfusion-induced infarct size (5, 12, 16, 20, 29), recovery of global or regional cardiac function (6, 7, 10, 18, 19, 24, 28, 31), or oxygen radical accumulation (28, 30, 31). Prior studies from our laboratory and others have shown that brief periods of ischemia to the heart (4, 14, 17) or brain (2), or hypoxia (1, 8), elicit a delayed upregulation of NO, which may play a role in mediating the second window of protection (4, 21, 27). Importantly, the majority of studies performed to date have used models of complete coronary artery occlusion. In the clinical setting, periods of myocardial ischemia in the presence of subtotal occlusion, i.e., CS rather than complete coronary artery occlusion, are more common.
The major finding of the current study, based on the differences observed in the same pigs studied with a similar CS in both the absence and presence of NO synthase inhibition, was that inhibition of NO abolished perfusion-contraction matching. Additionally, CS in the presence of NO synthase inhibition resulted in a more intense, prolonged stunning after reperfusion and in necrosis. There are two major mechanisms by which NO may affect perfusion-contraction matching: 1) by a protective effect in preventing necrosis and 2) altering myocardial metabolism and/or efficiency.
Our initial hypothesis was that the necrosis might be due to a more severe reduction in myocardial blood flow during CS after NO synthase inhibition, particularly because it has been shown that autoregulation in the heart is dependent in part on NO (26). Although there could not have been major transmural differences in blood flow due to the experimental design, i.e., coronary blood flow was reduced by ~40% during CS in both the absence and presence of NO synthase inhibition, it was possible that small areas of the subendocardium demonstrated a shift in blood flow distribution such that subendocardial blood flow was reduced more in the presence of NO synthase inhibition. Accordingly, we examined the frequency distribution of blood flow within the entire area at risk (9, 13) and found no evidence for a shift to a lower blood flow during CS. Thus NO-mediated coronary vasodilatation was not the protective mechanism, but rather these results suggest that NO elicits a protective effect on myocardial metabolism, potentially shifting the balance between O2 supply and demand.
It might be argued that the increase in LV systolic and aortic pressures observed after NO synthase inhibition caused an increase in myocardial oxygen consumption, which would result in more ischemic damage in response to any given reduction in blood flow. This is unlikely, because prior studies (3, 25) found no difference, not even a decrease, in oxygen consumption after systemic NO synthase inhibition. Nonetheless, to determine whether simply increased LV systolic and aortic pressures were responsible for the adverse effects of the L-NNA, we measured oxygen consumption in three pigs in the absence and presence of L-NNA, and we found oxygen consumption to be no different either at baseline or during CS.
An unexpected finding of the current investigation was that there was almost an immediate difference in the response of ischemic zone wall thickening during CS in the absence and presence of NO synthase inhibition. In the absence of L-NNA, the decrease in function early after CS roughly matched the decrease in blood flow. As the stenosis was maintained to keep blood flow reduced at a constant level, regional function deteriorated during the 1.5-h period of CS, most likely due to concomitant stunning (15). This gradual deterioration in ischemic zone wall thickening during the 1.5-h period of CS suggests a potential role for NO in mediating stunning during sustained CS. It is recognized that stunning is usually observed after complete cessation of blood flow and subsequent reperfusion. However, in this model blood flow is not completely abolished, but rather it is partially reduced, potentially allowing stunning to occur during the stenosis. In addition, the post-CS stunning was enhanced in the presence of L-NNA (as noted above), potentially due in part to the development of necrosis. The early deleterious effect on function was surprising because an upregulation of NO gene expression with concurrent protein translation could not have occurred this quickly. However, increased NO synthase activity can occur rapidly during ischemia independent of gene expression. This implies that the protective effects of NO on perfusion-contraction matching result in maintenance rather than downregulation of regional function, which could be related to a local action of NO on myocardial metabolism and/or efficiency. If this hypothesis is correct, then NO could exert a protective effect without altering oxygen consumption.
In summary, in response to myocardial ischemia induced by CS after NO synthase inhibition, the same reduction in coronary blood flow resulted in more severe regional myocardial dysfunction, enhanced post-CS stunning, and development of patchy necrosis. None of the adverse effects induced by CS after NO synthase inhibition were due to the level of coronary blood flow reduction, but they suggest an alteration in the flow-function relationship such that for any given flow reduction the resultant effects of ischemia are intensified, abolishing perfusion-contraction matching.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-59139, HL-33107, HL-33065, HL-37404, and HL-591417.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. F. Vatner, Henry H. Hood Research Program, Charles B. Degenstein Professor, Penn State College of Medicine, Weis Center for Research, 100 North Academy Ave., Danville, PA 17822.
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.
Received 16 February 2000; accepted in final form 6 April 2000.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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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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R. K. Kudej, X.-P. Zhang, B. Ghaleh, C.-H. Huang, J. B. Jackson, A. B. Kudej, N. Sato, S. Sato, D. E. Vatner, T. H. Hintze, et al. Enhanced cAMP-induced nitric oxide-dependent coronary dilation during myocardial stunning in conscious pigs Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2967 - H2974. [Abstract] [Full Text] [PDF]
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S.-J. Kim, R. K. Kudej, A. Yatani, Y.-K. Kim, G. Takagi, R. Honda, D. A. Colantonio, J. E. Van Eyk, D. E. Vatner, R. L. Rasmusson, et al. A Novel Mechanism for Myocardial Stunning Involving Impaired Ca2+ Handling Circ. Res., October 26, 2001; 89(9): 831 - 837. [Abstract] [Full Text] [PDF]
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