(Circulation. 1995;92:1005-1010.)
© 1995 American Heart Association, Inc.
Articles |
Endogenous and Exogenous Nitric Oxide Protect Against Intracoronary Thrombosis and Reocclusion After Thrombolysis
From the Cullen Cardiovascular Research Laboratory at Texas Heart Institute and the Departments of Internal Medicine and Pathology and Laboratory Medicine at the University of Texas-Houston Medical School, Houston, Tex; and the Division of Cardiology (P.G.), Second School of Medicine, University of Naples, Italy.
Correspondence to James T. Willerson, MD, Department of Internal Medicine, University of Texas-Houston Medical School, PO Box 20708, Houston, TX 77225.
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Abstract |
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Background Nitric oxide (NO), an endothelium-derived relaxing factor, plays an important role in regulating platelet activation. We evaluated the effect of NO in a canine model of intracoronary thrombosis, thrombolysis, and reocclusion.
Methods and Results Before thrombosis was induced, 34 anesthetized dogs were treated with a continuous intracoronary infusion of saline (n=8); NG-nitro-L-arginine (L-NNA, n=8), an inhibitor of NO synthetase; L-arginine (n=7), the precursor for NO; or sodium nitroprusside (SNP, n=11), an NO donor. Ten minutes after the infusion was begun, an electric current of 150 µA was applied to the endothelium of coronary arteries to induce thrombosis. Occlusive thrombi developed in all dogs in the saline group (38±4 minutes) and the L-NNA group (30±6 minutes), in 6 of 7 dogs in the L-arginine group (81±18 minutes), and in 6 of 11 dogs in the SNP group (102±21 minutes) (P<.01). The time to thrombus was prolonged by L-arginine (P<.05) and SNP (P<.01). After 3 hours of thrombus formation in coronary arteries, tissue plasminogen activator and heparin were administered intravenously. Thrombi were lysed in 4 (of 8) dogs in the saline group (71±8 minutes), in 4 (of 8) dogs in the L-NNA group (72±8 minutes), in 4 (of 6) dogs in the L-arginine group (50±14 minutes), and in 4 (of 6) dogs in the SNP group (49±11 minutes) (P>.05). After thrombolysis, coronary artery reocclusion developed in all reperfused dogs in the saline group (30±8 minutes) and in the L-NNA group (48±12 minutes), in 3 (of 4) reperfused dogs in the L-arginine group (123±26 minutes), and in 3 (of 4) reperfused dogs in the SNP group (128±19 minutes) (P<.01). The ex vivo platelet aggregation induced by collagen was inhibited after in vivo treatment with L-arginine or SNP.
Conclusions Increasing NO production or giving an NO donor may inhibit platelet aggregation and delay intracoronary thrombus formation and reocclusion after thrombolysis.
Key Words: endothelium-derived relaxing factors • platelets • thrombolysis • thrombosis • occlusions
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Many investigators believe that intracoronary thrombosis is important in the development of acute Q-wave myocardial infarction.1 2 3 Accordingly, thrombolytic therapy has been widely used to treat patients with acute myocardial infarction. The effectiveness of thrombolytic therapy in saving ischemic myocardium, improving left ventricular function, and reducing the mortality rate has been confirmed.4 5 6 However, the efficacy of thrombolytic therapy is limited by several factors, especially the reocclusion of coronary arteries after thrombolysis.7 8 Studies have shown that platelet and platelet-derived factors may play an important role in mediating reocclusion.9 10 11 12 One of the more promising attempts to increase the efficacy of thrombolytic therapy has been the use of antiplatelet drugs as adjuvant to thrombolytic agents.13 14 15 16 17
Nitric oxide, an endothelium-derived relaxing factor with antiplatelet function,18 19 20 21 is synthesized in the endothelial cells of the vessel walls. L-Arginine is the precursor for nitric oxide synthesis.22 Nitric oxide can also be released from nitrovasodilators, such as sodium nitroprusside, to exert its antiplatelet function.23 24 25 26 27 The effect of nitric oxide in protecting against arterial thrombosis has been studied previously.27 28 29 30 31 Some studies also have explored the possible synergistic effect between nitric oxide and thrombolytic agents.32 33 However, the effect of nitric oxide on thrombolysis and coronary artery reocclusion after thrombolysis is not yet well elucidated.
This study was designed to test the hypothesis that both endogenous and exogenous nitric oxide protect against intracoronary thrombosis and coronary artery reocclusion after thrombolysis. We used a canine model in which thrombosis was induced in the coronary arteries by electric current. We attempted to reduce or to promote the synthesis of endogenous nitric oxide and to add exogenous nitric oxide.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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All procedures used in this study were conducted according to the principles of the American Physiological Society and were approved by the Institutional Animal Care and Use Committee at the Texas Heart Institute, Houston, Tex.
Surgical Preparation
Mongrel dogs (n=34) weighing 25
to 35 kg were
anesthetized with sodium pentobarbital (30 mg/kg IV),
intubated, and connected to a mechanical respirator (Harvard model 60).
Plastic catheters were placed in a carotid artery to monitor aortic
pressure and in a jugular and a peripheral vein to
administer drugs and fluids. A left fifth intercostal space thoracotomy
was performed, and the heart was suspended in a pericardial cradle. A
1- to 2-cm segment of left anterior descending coronary artery
(LAD) was carefully exposed, and nearby branches were ligated. An
ultrasonic Doppler flow probe (Hartley Instruments) was placed
around the proximal portion of the exposed LAD to measure the velocity
of blood flow. A plastic catheter was placed in the LAD proximal to the
flow probe to administer drugs (Fig 1
). Baseline
hemodynamics, including heart rate, systolic and
diastolic aortic pressures, and phasic and mean
coronary blood flow velocities, were recorded on an
eight-channel recorder (Gould, model 3000).
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Experimental Procedures
After baseline hemodynamics were
recorded,
LADs were infused in four different groups of animals: 8 dogs were
infused with saline; to eliminate the production of
endogenous nitric oxide, 8 dogs were infused with
NG-nitro-L-arginine (L-NNA, Sigma),
an inhibitor of nitric oxide synthetase, at 1
µg · kg-1 ·min-1; to
promote the
production of endogenous nitric oxide, 7 dogs were
infused with L-arginine (Sigma), the precursor for nitric
oxide, at 100
µg · kg-1 · min-1;
and to provide exogenous nitric oxide, 11 dogs were infused with sodium
nitroprusside, a donor of nitric oxide, at 1
µg · kg-1 · min-1. The
various
treatments were infused directly into the coronary arteries to
effect a high local concentration. The infusion rates were chosen after
preliminary studies in our laboratory had established them as effective
for the desired result.28 30 The treatments were
continued
to the end of the study.
Ten minutes after the beginning of each
treatment, a needle electrode
(a 25-gauge needle crimped on the end of a 10-cm length of 30-gauge,
Teflon-insulated, silver wire) was inserted obliquely approximately 4
mm into the lumen of the exposed LAD at the site distal to the
Doppler flow probe. The needle was stabilized on the vessel with
6-0 silk suture. To prevent the electric current from damaging the
surrounding tissue, the needle/wire and soldered connection were
covered with heat-shrink tubing. A ground wire was connected to the
subcutaneous tissue to complete the electrical circuit. To induce
thrombosis, a current of 150 µA was delivered through the electrode
connected in series with the positive terminal of a 9-V battery, a
50-k
potentiometer, a multimeter, and a ground wire (Fig
1
).
Thrombus formation was determined by the reduction of coronary
blood flow velocity, which was monitored by the externally positioned
Doppler flow probe. The time that elapsed between the beginning of
the electrical stimulation and the formation of an occlusive thrombus
was recorded as thrombosis time. Electric current was delivered
continuously until 30 minutes after persistent thrombotic occlusion had
occurred.
The thrombus formed in the coronary arteries was allowed to mature for 3 hours. The animals were then treated with tissue plasminogen activator (TPA; Genentech) as an intravenous bolus (80 µg/kg) and as a 90-minute continuous infusion (8 µg · kg-1 · min-1) and heparin as a bolus (200 U/kg). Afterward, animals were monitored continuously to determine when thrombi were lysed, that is, when the flow velocity of the coronary artery returned to at least 70% of the value that existed before the thrombus was formed. The time from administration of TPA to thrombolysis (and consequent reperfusion) was recorded as thrombolysis or reperfusion time. Dogs in which thrombi were not lysed after 90 minutes of TPA infusion were excluded from further study. The reperfused dogs were monitored until the coronary arteries reoccluded or until 180 minutes after reperfusion if reocclusion did not occur during that period. The time from thrombolysis/reperfusion to reocclusion was recorded as reocclusion time. Dogs in which coronary arteries had not reoccluded after 180 minutes of reperfusion were considered not to have reoccluded. Dogs whose coronary arteries did reocclude were monitored for 30 minutes more to document persistent reocclusion.
Nitrite Measurement
The amount of nitric oxide in the
coronary circulation
was determined by measuring nitrite in plasma from blood taken from the
coronary sinus. Blood samples were collected from 2 dogs in
each group before the LADs were injured and 10, 30, 60, and 180 minutes
after saline, L-NNA, L-arginine, or sodium nitroprusside
treatments were begun. Nitrite concentration was measured using the
Greiss reagent.34
Hematocrit, Coagulation, and Platelet Aggregation
Studies
Hematocrit was measured before and immediately after TPA was
administered. Activated whole blood clotting time was measured
on an automated blood coagulation timing device (HemoTec 2001370)
before and at 5 and 60 minutes after TPA was administered.
Ex vivo platelet aggregation was analyzed before and 10 minutes after L-NNA, L-arginine, or sodium nitroprusside was administered. Blood samples were collected from a catheter in the coronary sinus and placed into plastic tubes containing a 3.8% solution of sodium citrate (9 vol blood:1 vol sodium citrate). Platelet-rich plasma was obtained by centrifuging blood samples at 200g for 20 minutes, and platelet-poor plasma was obtained by centrifuging the residual blood at 3000g for 10 minutes. A four-channel platelet aggregometer (Bio-Data, model PAP-4) was used for the assay. Collagen (Sigma) at 5, 10, and 20 µg/mL was used to induce platelet aggregation. The degree of platelet aggregation was reported as a percentage of maximal increase of light transmission in platelet-rich plasma. Platelet-poor plasma was used as the standard for 100% light transmission.
Statistical Analyses
All values are expressed as
mean±SEM. Fisher's exact test was
used to compare the frequency of thrombosis, thrombolysis,
and reocclusion in different groups of animals. A one-way ANOVA was
used to compare the time to thrombosis, thrombolysis, and
reocclusion of coronary arteries in different groups of animals
and the hemodynamics and activated clotting
times obtained from different time periods. The Student's t
test was used to compare the percentage of platelet aggregation and
hematocrit values before and after treatment. A probability value of
less than .05 was considered significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Thrombosis
The initial treatment with intracoronary infusion of saline and L-arginine did not significantly change heart rate, aortic pressure, or blood flow velocity in coronary arteries. L-NNA administration increased mean aortic pressure by 10 to 20 mm Hg and slightly decreased heart rate and coronary flow velocity. Sodium nitroprusside infusion decreased mean aortic pressure by 10 to 15 mm Hg and slightly increased heart rate and coronary flow velocity.
After electric current was begun in the
endothelium of
the LAD, occlusive thrombi developed in 8 dogs (100%) in the saline
group in 38±4 minutes and in 8 dogs (100%) in the L-NNA group in
30±6 minutes (compared with saline-treated dogs, P>.05)
(Fig 2). Occlusive thrombi also developed in 6 of 7 dogs
(86%) in the L-arginine group and in 6 of 11 dogs (55%)
in the sodium nitroprusside group (compared with saline-treated dogs,
P<.05). Thrombosis time was 81±18 minutes in the
L-arginine group (compared with saline-treated dogs,
P<.05) and 102±21 minutes in the sodium nitroprusside
group (compared with saline-treated dogs, P<.01) (Fig
2).
One L-arginine–treated dog and 5 sodium
nitroprusside–treated dogs did not develop occlusive thrombi during 3
hours of continuous electrical stimulation in the coronary
arteries.
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Thrombolysis
Three hours after coronary arteries were
occluded by
thrombi, TPA and heparin were administered intravenously.
Thrombolysis occurred in 4 of 8 dogs (50%) in the saline
group in 71±8 minutes and in 4 of 8 dogs (50%) in the L-NNA group in
72±8 minutes (compared with saline-treated dogs, P>.05)
(Fig 3). Thrombolysis occurred in 4 of 6
dogs (67%) in the L-arginine group and in 4 of 6 dogs
(67%) in the sodium nitroprus-side group (compared with
saline-treated dogs, P>.05). Thrombolysis time was 50±14
minutes in the L-arginine group and 49±11 minutes in the
sodium nitroprusside group (compared with saline-treated dogs, both
groups P>.05) (Fig 3).
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Mild bleeding was observed around surgical incisions 20 to 30 minutes after TPA was administered. There were no significant differences in thrombolysis times among the four groups of animals. Heart rates and aortic pressures did not change significantly during thrombolysis.
Reocclusion
After thrombolysis, the reperfused coronary
arteries reoccluded in all dogs (100%) in the saline and L-NNA
groups, in 3 of 4 dogs (75%) in the L-arginine
group, and in 3 of 4 dogs (75%) in the sodium nitroprusside group.
Reocclusion time was 30±8 minutes in the saline group and 48±12
minutes in the L-NNA group (P>.05) (Fig 4).
Reocclusion time was 123±26 minutes in the
L-arginine group and 128±19 minutes in the sodium
nitroprusside group (compared with saline-treated dogs, both groups
P<.01) (Fig 4). Cyclic flow variations developed in
most
animals before the coronary arteries became totally reoccluded.
There were no significant differences in the frequency of cyclic flow
variations among the four groups of animals.
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Nitrite Level in Coronary Circulation
The nitrite (nitric
oxide product) level was measured in the
plasma of blood collected from the coronary sinus before
electrical injury and after each treatment. In both saline-treated and
L-NNA–treated animals, the nitrite concentration decreased gradually
(Table 1). However, nitrite concentrations increased at
some time points after animals were treated with L-arginine
or sodium nitroprusside (Table 1).
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Coagulation Time, Hematocrit, and Ex Vivo Platelet
Aggregation
Immediately after TPA and heparin were administered,
activated clotting time was significantly prolonged (Table 2).
One hour later, it had returned to a level 1.5 to 2
times the baseline value. There were no significant differences in
activated clotting time among the four groups of dogs (Table
1). Hematocrit did not change significantly after treatment
with
thrombolytic agents (before versus after: 40±1% versus
40±2% in the saline group, 38±2% versus 39±1% in the
L-NNA group,
39±1% versus 39±1% in the L-arginine group, and
38±2%
versus 37±1% in the sodium nitroprusside group).
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Collagen
induced a dose-dependent platelet aggregation in
platelet-rich plasma obtained from coronary sinus blood
before L-NNA, L-arginine, or sodium nitroprusside was
administered (Fig 5). Intracoronary
administration of L-NNA did not significantly affect collagen-induced
platelet aggregation, whereas administration of
L-arginine and sodium nitroprusside inhibited platelet
aggregation induced by a low concentration of collagen (Fig 5).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The data from this study demonstrate that intracoronary administration of L-arginine, the precursor for nitric oxide synthesis, or sodium nitroprusside, a nitric oxide–containing vasodilator, delays thrombosis formation and reocclusion after thrombolysis in endothelium-injured canine coronary arteries.
Nitric oxide, identified as endothelium-derived relaxing factor,18 is synthesized by endothelial cells from the terminal guanidino nitrogen atoms of L-arginine.22 Under normal circumstances, endothelial cells constantly release nitric oxide35 ; both the synthesis and the release of nitric oxide are promoted by stimulants, such as acetylcholine.35 36 The synthesis and release of nitric oxide are also increased by increasing the amount of precursor, L-arginine.35 37 In addition, nitrovasodilators, such as sodium nitroprusside, may be metabolized in the vessel wall and release nitric oxide as an exogenous source.25
Nitric oxide is a major regulator of vessel tone,35 but recent studies have found that it also has other important functions.19 Among these, inhibiting platelet activation is important in regulating hemostasis and thrombosis.19 We and others have shown that blocking the production of nitric oxide promotes mechanical injury–induced arterial thrombosis, whereas increasing the synthesis of nitric oxide or providing exogenous nitric oxide protect against arterial thrombosis.28 29 30 In this study, thrombosis was induced by electrically injuring the endothelium of coronary arteries. Intracoronary administration of L-NNA, an inhibitor of nitric oxide synthetase, reduced thrombosis time from 38 minutes (in control dogs) to 30 minutes, whereas L-arginine increased thrombosis time to 81 minutes, and sodium nitroprusside increased thrombosis time to 101 minutes. In almost 50% of the animals treated with sodium nitroprusside, thrombosis did not develop at all. The ex vivo platelet aggregation in platelet-rich plasma obtained from coronary sinus blood was also inhibited after the treatments with L-arginine and sodium nitroprusside. These results are consistent with our own and those of others who have previously shown that both endogenous and exogenous nitric oxide protect against arterial thrombosis.28 29 30
After an arterial thrombus has formed, administration of thrombolytic agents, such as TPA, recanalizes the occluded artery and reperfuses ischemic tissues. In an effort to increase thrombolysis, antiplatelet agents have been added to thrombolytic agents and have been somewhat effective.38 39 40 41 In this study, L-arginine and sodium nitroprusside shortened thrombolysis time only slightly. The slight effect of these agents may have been a result of the concomitant use of heparin, which also enhances thrombolysis and may have made further improvement difficult.42 This hypothesis is supported by the failure of other antiplatelet agents such as ridogrel, a thromboxane synthetase inhibitor and receptor antagonist, and clopidogrel, a potent inhibitor of ADP-induced platelet aggregation, to reduce the time required for thrombolysis in a similar experimental model.11 12
Reocclusion of the recanalized coronary arteries limits the efficacy of thrombolytic therapy,7 8 and the causes of reocclusion are not yet fully understood. Reocclusion may be initiated when the residual thrombus activates platelets.9 10 11 12 Reperfusion also may generate large amounts of active oxygen species,43 which may in turn enhance platelet aggregation.44 Active oxygen species also may damage the endothelium of arteries and destroy nitric oxide, which would in turn promote platelet activation.45 46 Therefore, the reocclusion of coronary arteries after thrombolysis may be enhanced by the generation of active oxygen species and the dysfunction of endothelium. Increasing the production of nitric oxide or providing exogenous nitric oxide should protect against reocclusion. This hypothesis is supported by the present study, because treatment with L-arginine and sodium nitroprusside significantly prolonged reocclusion time.
In a previous study, we observed that in more than 70% of the cases, sodium nitroprusside eliminated the periodic formation of thrombus associated with platelet aggregation in mechanically injured arteries.28 In this study, however, the intracoronary administration of L-arginine or sodium nitroprusside delayed but did not completely prevent the formation of thrombus and consequent reocclusion of the coronary artery. This difference in results may reflect a difference between the mechanism of initial arterial thrombosis and that of reocclusion after thrombolysis. To compensate for the inability of nitric oxide to completely prevent reocclusion after thrombolysis, it may be necessary to combine a nitric oxide precursor or donor with another antiplatelet drug, such as aspirin, or a more potent inhibitor of platelet aggregation, such as an inhibitor of the platelet glycoprotein IIb/IIIa receptors. In addition, thrombin is another important mediator in the development of reocclusion.11 38 47 48 49 The heparin used in this study was given as a bolus, which could have caused a rebound of platelet activation in 2 to 3 hours.50 A concomitant continuous infusion of heparin at low dose may be useful in preventing reocclusion.
Also in this study, the administration of L-NNA did not significantly affect reocclusion. L-NNA blocks the synthesis of nitric oxide and in theory should therefore enhance platelet activation and reocclusion after thrombolysis. It seems likely that after endothelial injury, reperfusion, or both, the dysfunctional endothelium has already lost much of its ability to produce nitric oxide. In this case, the addition of L-NNA to block the synthesis of nitric oxide produces no further effect. The reduction in the nitrite concentration in the coronary circulation after treatment with both saline and L-NNA supports this hypothesis.
Conclusions
Nitric oxide plays an important role in
protecting against
platelet activation and arterial thrombosis and
reocclusion after thrombolysis. Enhancing the
production of endogenous nitric oxide by
L-arginine or providing exogenous nitric oxide by sodium
nitroprusside may diminish thrombus formation and reocclusion of
coronary arteries after thrombolysis.
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Acknowledgments |
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This work was supported by NHLBI Ischemic SCOR grant HL-17669, NIH RO1-HL-50179-01, and RO1-HL45944-04. We thank Jerry Eastman, MS, ELS, for editorial assistance.
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Footnotes |
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Valentin Fuster, MD, PhD, Mount Sinai Medical Center, New York, NY, is Guest Editor.
Received August 15, 1994; revision received February 6, 1995; accepted February 19, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984;310:1137-1140. [Abstract]
2.
Kragel AH, Reddy SG, Wittes JT, Roberts WC.
Morphometric analysis of the composition of
atherosclerotic plaques in four major epicardial coronary
arteries in acute myocardial infarction and in sudden coronary
death. Circulation. 1989;80:1747-1756.
3. Mizuno K, Satomura K, Miyamoto A, Arakawa K, Shibuya T, Arai T, Kurita A, Nakamura H, Ambrose JA. Angioscopic evaluation of coronary artery thrombi in acute coronary syndromes. N Engl J Med. 1992;326:287-291. [Abstract]
4.
Gersh BJ, Anderson JL. Thrombolysis
and myocardial salvage: results of clinical trials and the animal
paradigm-paradoxic or predictable?
Circulation. 1993;88:296-306.
5. Midgette AS, O'Connor GT, Baron JA, Bell J. Effect of intravenous streptokinase on early mortality in patients with suspected acute myocardial infarction: a meta-analysis by anatomic location of infarction. Ann Intern Med. 1990;113:961-968.
6. Wilcox RG, Von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet. 1988;2:525-530. [Medline] [Order article via Infotrieve]
7.
Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith
C, Ellis S, Sigmon KN, Kereiakes D, George B, Stack R.
Consequences of reocclusion after successful reperfusion therapy
in acute myocardial infarction: TAMI Study Group.
Circulation. 1990;82:781-791.
8. Lim MJ, Gallagher MA, Ziadeh M, Buda AJ. Effect of coronary reocclusion after initial reperfusion on ventricular function and infarct size. J Am Coll Cardiol. 1991;18:879-885. [Abstract]
9.
Golino P, Ashton JH, Glas-Greenwalt P, McNatt J, Buja
LM, Willerson JT. Mediation of reocclusion by
thromboxane A2 and serotonin after
thrombolysis with tissue-type plasminogen
activator in a canine preparation of coronary
thrombosis. Circulation. 1988;77:678-684.
10.
Fitzgerald DJ, Fitzgerald GA. Role of thrombin
and thromboxane A2 in reocclusion following
coronary thrombolysis with tissue-type
plasminogen activator. Proc
Natl Acad Sci U S A. 1989;86:7585-7589.
11.
Yao SK, Ober JC, Ferguson JJ, Anderson HV, Maraganore
J, Buja LM, Willerson JT. Combination of inhibition of thrombin
and blockade of thromboxane A2 synthetase and
receptors enhances thrombolysis and delays reocclusion in
canine coronary arteries.
Circulation. 1992;86:1993-1999.
12.
Yao SK, Ober JC, Ferguson JJ, Maffrand JP, Anderson HV,
Buja LM, Willerson JT. Clopidogrel is more effective than
aspirin as an adjuvant treatment to prevent reocclusion after
thrombolysis. Am J Physiol. 1994;267:H488-H493.
13. Roux S, Christeller S, Ludin E. Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis. J Am Coll Cardiol. 1992;19:671-677. [Abstract]
14. Kleiman NS, Ohman EM, Califf RM, George BS, Kereiakes D, Aguirre FV, Weisman H, Schaible T, Topol EJ. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy: results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study. J Am Coll Cardiol. 1993;22:381-389. [Abstract]
15. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med. 1990;323:1433-1437. [Abstract]
16. Cannon CP, McCabe CH, Henry TD, Schweiger MJ, Gibson RS, Mueller HS, Becker RC, Kleiman NS, Haugland M, Anderson JL, Sharaf BL, Edwards SJ, Rogers WJ, Williams DO, Braunwald E. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J Am Coll Cardiol. 1994;23:993-1003. [Abstract]
17.
RAPT Investigators. Randomized trial of
ridogrel, a combined thromboxane A2 synthase
inhibitor and thromboxane
A2/prostaglandin
endoperoxide receptor antagonist, versus
aspirin as adjunct to thrombolysis in patients with acute
myocardial infarction: the Ridogrel versus Aspirin Patency Trial
(RAPT). Circulation. 1994;89:588-595.
18. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526. [Medline] [Order article via Infotrieve]
19.
Moncada S, Higgs A. The
L-arginine-nitric oxide pathway. N
Engl J Med. 1993;329:2002-2012.
20. Radomski MW, Palmer RMJ, Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun. 1987;148:1482-1489. [Medline] [Order article via Infotrieve]
21.
Mendelsohn ME, O'Neill S, George D, Loscalzo J.
Inhibition of fibrinogen binding to human platelets by
S-nitroso-N-acetylcysteine.
J Biol Chem. 1990;265:19028-19034.
22.
Sakuma I, Stuehr DJ, Gross SS, Nathan C, Levi R.
Identification of arginine as a precursor of
endothelium-derived relaxing factor. Proc
Natl Acad Sci U S A. 1988;85:8664-8667.
23.
Kowaluk EA, Seth P, Fung HL.
Metabolic activation of sodium nitroprusside to
nitric oxide in vascular smooth muscle. J
Pharmacol Exp Ther. 1992;262:916-922.
24. Marks GS, McLaughlin BE, Brown LB, Beaton DE, Booth BP, Nakatsu K, Brien JF. Interaction of glycerol trinitrate and 10,000 x g supernatant: biotransformation and nitric oxide formation. Can J Physiol Pharmacol. 1991;69:889-892. [Medline] [Order article via Infotrieve]
25. Feelisch M. The biochemical pathways of nitric oxide formation from nitrovasodilators: appropriate choice of exogenous NO donors and aspects of preparation and handling of aqueous NO solutions. J Cardiovasc Pharmacol. 1991;17(suppl 3):S25-S33.
26. Stamler JS, Loscalzo J. The antiplatelet effect of organic nitrates and related nitroso compounds in vitro and in vivo and their relevance to cardiovascular disorders. J Am Coll Cardiol. 1991;18:1529-1536. [Abstract]
27.
Folts JD, Stamler J, Loscalzo J.
Intravenous nitroglycerin infusion
inhibits cyclic blood flow responses caused by periodic platelet
thrombus formation in stenosed canine coronary
arteries. Circulation. 1991;83:2122-2127.
28.
Yao SK, Ober JC, Krishnaswami A, Ferguson JJ, Anderson
HV, Golino P, Buja LM, Willerson JT. Endogenous
nitric oxide protects against platelet aggregation and cyclic flow
variations in stenosed and endothelium-injured
arteries. Circulation. 1992;86:1302-1309.
29.
Golino P, Cappelli-Bigazzi M, Ambrosio G, Ragni M,
Russolillo E, Condorelli M, Chiariello M.
Endothelium-derived relaxing factor modulates
platelet aggregation in an in vivo model of recurrent platelet
activation. Circ Res. 1992;71:1447-1456.
30. Yao SK, Igo SR, Ober JC, Clubb FJ, Macris MP, Ferguson JJ, Anderson HV, Buja LM, Willerson JT. Localized administration of a nitric oxide donor is more effective than its systemic infusion in protecting against platelet aggregation in stenosed and endothelium-injured coronary arteries. Clin Res. 1994;42:163A. Abstract.
31.
Groves PH, Lewis MJ, Cheadle HA, Penny WJ. SIN-1
reduces platelet adhesion and platelet thrombus formation in a
porcine model of balloon angioplasty.
Circulation. 1993;87:590-597.
32. Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction: value of combined thrombolytic and vasodilator therapy. N Engl J Med. 1987;317:1055-1059. [Abstract]
33.
Stamler JS, Vaughan DE, Loscalzo J. Synergistic
disaggregation of platelets by tissue-type plasminogen
activator, prostaglandin E1,
and nitroglycerin. Circ
Res. 1989;65:796-804.
34. Scott-Burden T, Elizondo E, Ge T, Boulanger CM, Vanhoutte PM. Simultaneous activation of adenylyl cyclase and protein kinase C induces production of nitric oxide by vascular smooth muscle cells. Mol Pharmacol. 1994;46:274-282. [Abstract]
35.
Kelm M, Schrader J. Control of coronary
vascular tone by nitric oxide. Circ Res. 1990;66:1561-1575.
36. Amezcua JL, Dusting GJ, Palmer RMJ, Moncada S. Acetylcholine induces vasodilation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator. Br J Pharmacol. 1988;95:830-834. [Medline] [Order article via Infotrieve]
37.
Panza JA, Casino PR, Badar DM, Quyyumi AA.
Effect of increased availability of
endothelium-derived nitric oxide precursor on
endothelium-dependent vascular relaxation in normal
subjects and in patients with essential hypertension.
Circulation. 1993;87:1475-1481.
38.
Yao SK, McNatt J, Anderson HV, Eidt J, Cui K, Golino P,
Glas-Reenwalt P, Maraganore J, Buja LM, Willerson JT. Thrombin
inhibition enhances tissue-type plasminogen
activator-induced thrombolysis and delays
reocclusion. Am J Physiol. 1992;262:H374-H379.
39.
Yao SK, Ober JC, Garfinkel LI, Hagay Y, Ezov N,
Ferguson JJ, Anderson HV, Panet A, Gorecki M, Buja LM, Willerson JT.
Blockade of platelet membrane glycoprotein Ib
receptors delays intracoronary thrombogenesis, enhances
thrombolysis, and delays coronary artery
reocclusion in dogs. Circulation. 1994;89:2822-2828.
40.
Haskel EJ, Prager NA, Sobel BE, Abendschein DR.
Relative efficacy of antithrombin compared with
antiplatelet agents in accelerating coronary
thrombolysis and preventing early reocclusion.
Circulation. 1991;83:1048-1056.
41.
Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT,
Guerrero JL, Leinbach RC, Ziskind AA, Collen D. Rapid and
sustained coronary artery recanalization
with combined bolus injection of recombinant tissue-type
plasminogen activator and monoclonal
antiplatelet GPIIb/IIIa antibody in a canine
preparation. Circulation. 1988;77:670-677.
42.
Cercek B, Lew AS, Hod H, Yano J, Reddy NK, Ganz W.
Enhancement of thrombolysis with tissue-type
plasminogen activator by pretreatment with
heparin. Circulation. 1986;74:583-587.
43. Babbs CF, Cregor MD, Turek JJ, Badylak SF. Endothelial superoxide production in the isolated rat heart during early reperfusion after ischemia: a histochemical study. Am J Pathol. 1991;139:1069-1080. [Abstract]
44.
Yao SK, Ober JC, Gonenne A, Clubb FJ, Krishnaswami A,
Ferguson JJ, Anderson HV, Gorecki M, Buja LM, Willerson JT.
Active oxygen species play a role in mediating platelet
aggregation and cyclic flow variations in severely stenosed and
endothelium-injured coronary arteries.
Circ Res. 1993;73:952-967.
45. Gryglewski RJ, Palmer RMJ, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986;320:454-456. [Medline] [Order article via Infotrieve]
46.
Mehta JL, Lawson DL, Nichols WW. Attenuated
coronary relaxation after reperfusion: effects of
superoxide dismutase and TxA2 inhibitor
U63557A. Am J Physiol. 1989;257:H1240-H1246.
47.
Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L,
Fuster V. Effects of thrombin inhibition on the development of
acute platelet-thrombus deposition during angioplasty in pigs:
heparin versus recombinant hirudin, a specific thrombin
inhibitor. Circulation. 1989;79:657-665.
48.
Heras M, Chesebro JH, Webster MWI, Mouk JS, Grill DE,
Penny WJ, Bowie EJW, Badimon L, Fuster V. Hirudin, heparin, and
placebo during deep arterial injury in the pig: the in vivo
role of thrombin in platelet-mediated thrombosis.
Circulation. 1990;82:1476-1484.
49. Meyer B, Badimon J, Fuster V, Mailhac A, Fernandez-Ortiz A, Chesebro J, Badimon L. Inhibition of the progression of thrombus growth on pre-existing mural thrombus: targeting optimal therapy. J Am Coll Cardiol. 1994;23(2 suppl A):64A. Abstract.
50. Theroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med. 1992;327:141-145.[Abstract]
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