© 1996 American Heart Association, Inc.
Articles |
Platelet Activation in Acute Myocardial Infarction and Unstable Angina Is Inhibited by Nitric Oxide Donors
From the Cardiology Department (E.J.L., R.J.W.), King's College Hospital, and the Department of Medicine (E.J.L., J.F.M.), King's College School of Medicine, London, England.
Correspondence to Prof J.F. Martin, Professor of Cardiovascular Science, Department of Medicine, King's College School of Medicine, Bessemer Rd, London SE5 9PJ, UK.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Abstract Platelet activation and thrombus formation within the coronary artery are major factors in acute myocardial infarction (AMI) and unstable angina (UA), and continuing platelet activation is associated with an adverse prognosis. We assessed platelet activation by using flow cytometry to measure platelet surface expression of P-selectin and glycoprotein IIb/IIIa in 20 patients with AMI and 20 with UA, all of whom were treated with aspirin. Platelet studies were repeated after the infusion of a nitric oxide donor (glyceryl trinitrate or S-nitrosoglutathione) that produced a fall in mean arterial pressure of no more than 10 mm Hg. P-selectin was expressed on 2.5% (range, 1.4% to 6.3%) of platelets from AMI and 2.3% (range, 1.6% to 3.3%) from UA subjects compared with 1.0% (range, 0.6% to 1.9%) of platelets from 20 control volunteers without angina (P<.001). Glycoprotein IIb/IIIa expression was 101.6±2.7 arbitrary units of relative fluorescence in AMI and 100.2±3.3 in UA compared with 87.8±2.5 in control subjects (P<.01). In both AMI and UA, S-nitrosoglutathione reduced P-selectin (P<.001) and glycoprotein IIb/IIIa (P<.05) expression, as did glyceryl trinitrate (P<.02 and P<.01, respectively). In 3 of 20 patients receiving glyceryl trinitrate the lowest dose was not tolerated due to headache or hypotension. These findings show that platelet activation persists in AMI and UA despite aspirin treatment and that this can be inhibited by using glyceryl trinitrate or S-nitrosoglutathione. S-nitrosoglutathione is better tolerated at the doses required.
Key Words: myocardial infarction • unstable angina • platelets • nitric oxide
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Both AMI and UA are characterized by the formation of thrombus within the coronary artery,1 2 3 and systemic platelet secretion and increased aggregability have been demonstrated in both conditions.4 5 6 7 Continuing platelet hyperreactivity is a marker for mortality and further cardiac events in survivors of MI8 and is associated with further events in UA.5
Most platelet studies in AMI and UA have been performed on patients
not taking aspirin. Anti-platelet treatment with aspirin is
effective in reducing mortality in patients with MI and
UA,9 10 but there is evidence that platelet
activation
persists in AMI despite aspirin treatment.11 Aspirin,
which inhibits platelet thromboxane A2
production, is an effective inhibitor of
platelet aggregation in vivo. However, NO, which increases cyclic
GMP, is a potent inhibitor of both platelet
aggregation12 and adhesion13 in addition to
being a vasodilator. Although early studies using the NO donor GTN
failed to demonstrate inhibition of platelet aggregation at
therapeutic doses,14 more recent evidence suggests that
GTN does inhibit platelets in vivo.15 GSNO is an NO
donor with a preferential action on platelets16 17
and
an effective inhibitor of platelet activation in humans
at doses causing no hemodynamic effect.18
The degree of platelet activation can be assessed by measuring
platelet surface expression of the 
-granule protein
P-selectin (CD62/GMP140) and the fibrinogen receptor GPIIb/IIIa
(IIbß3) by using flow cytometry. The aims
of this study were to assess platelet activation by using flow
cytometry in patients with AMI and UA treated with aspirin and to
determine whether this platelet activation could be inhibited by
using GTN or GSNO.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patients
Twenty patients were studied within 48 hours of onset of AMI, which was diagnosed by the presence of typical chest pain with ST-segment elevation and a rise in creatine phosphokinase to 2.5 times normal. The median time from onset of pain was 25.5 (range, 7 to 41) hours. Twenty patients with UA (class IIIb),19 defined as new onset or sudden worsening of angina occurring at rest or on minimal exertion within the past 48 hours, with ST-segment depression or T-wave inversion and no rise in creatine phosphokinase, were also studied. The median duration of UA was 7 (range, 2 to 49) days. Patients with previous coronary angioplasty or bypass grafting were excluded, as were those with MI within the preceding 6 months and those diagnosed with three-vessel coronary disease or long-standing angina of greater than New York Heart Association functional class 2. All patients had received aspirin 300 mg PO, and those with AMI had also received streptokinase 1.5 mU IV. Intravenous nitrates were stopped at least 1 hour prior to the study. The control group comprised 20 volunteers with either no history of chest pain or angiographically normal coronary arteries. All subjects gave fully informed consent, and the study was approved by the ethics committee of King's College Hospital.
Study Protocol
A 1.8-mL blood sample obtained from each
subject from an
antecubital vein and drawn into a syringe containing 0.2 mL of
3.15% trisodium citrate was processed immediately for
flow cytometry. Throughout the study patients remained supine, and
blood pressure was measured every 3 minutes by using an automated cuff.
An initial prestudy period of at least 20 minutes demonstrated stable
blood pressure. Patients were divided sequentially into two groups and
received either GTN or GSNO dissolved in normal saline given via a
peripheral vein at an initial rate of 7.5 mL/h IV. The
starting dose of GTN was 1.1
nmol·kg-1·min-1 and of GSNO,
2.2
nmol·kg-1·min-1. Infusion
continued
initially for 15 minutes. If there was no change in mean
arterial blood pressure after 15 minutes, then the rate was
doubled for an additional 15 minutes to a maximum of 45 minutes. If the
mean arterial pressure fell 5 to 10 mm Hg, the low-dose
infusion was continued; if the mean arterial pressure fell
10 mm Hg or if the patient wished to discontinue the study due to any
symptoms, the infusion was stopped. At the end of the infusion, once
the blood pressure had returned to baseline, a further blood sample was
taken for flow cytometry.
Flow Cytometry
Aliquots of 5 µL whole blood were
immediately incubated at
room temperature with a saturating concentration of FITC-labeled mouse
anti-human P-selectin IgG (Immunotech) or mouse anti-human
GPIIIa IgG (Dako) and phycoerythrin-labeled mouse anti-human
GPIb IgG (Dako), with an isotype-matched mouse IgG raised against
Aspergillus niger glucose oxidase (Dako) as a negative
control. After 5 minutes ice-cold Tyrode's solution was added, and
the samples were analyzed by using a
fluorescence-activated cell sorter flow cytometer
(Becton Dickinson) with LYSIS II software. The cell sorter
was calibrated daily with fluorescent microbead standards
(Becton Dickinson). The platelet population was analyzed at
a low flow rate and identified based on the forward- and
side-scatter characteristics and the expression of GPIb, which is
not found on other circulating blood cells (Fig 1
). For
each sample 10 000 platelets were collected. P-selectin, a
platelet -granule protein, is expressed only on the
platelet surface following activation. Therefore, after incubation
with FITC-labeled P-selectin antibody, the percentage of platelets
positive for P-selectin was determined by the number that had FITC
fluorescence >99% of those platelets incubated with the
nonspecific antibody. GPIIb/IIIa, the fibrinogen receptor, is expressed
on all platelets, and surface expression increases with
platelet activation. GPIIb/IIIa antibody binding was therefore
measured, in arbitrary units, as the relative fluorescence
intensity per platelet.
|
Statistics
Values for P-selectin are not normally distributed
and are
expressed as median and range. Comparisons between AMI, UA, and control
subjects were made by using the Kruskal-Wallis and Mann-Whitney
U tests. Because values are normally distributed for
GPIIb/IIIa, results are expressed as mean±SEM. Statistical differences
were determined by ANOVA and Student's t test. For
pretreatment and posttreatment comparisons the numbers were smaller,
and Wilcoxon paired tests were used throughout; a value of
P<.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patients' and control subjects' characteristics were similar apart from a greater number of smokers in the AMI and UA groups (see Table
). In the AMI group receiving GTN the final
doses were 1.1 nmol·kg-1·min-1
in 7
patients and 2.2 in 2; 1 patient did not tolerate the starting dose due
to severe headache. In the UA group receiving GTN the final doses were
1.1 nmol·kg-1·min-1 in 7
patients and
2.2 in 1; 2 patients did not tolerate the starting dose due to a fall
in mean arterial blood pressure >10 mm Hg. In the AMI
group receiving GSNO the final dose was 2.2
nmol·kg-1·min-1 in 7 patients
and 4.4
in 3; in the UA group the doses were 2.2
nmol·kg-1·min-1 in 4 patients,
4.4 in
5, and 8.8 in 1. The only symptom reported in the patients receiving
GSNO was mild flushing in 2 patients at the highest dose received.
Preceding oral medication could not be discontinued for the study. In
the AMI group, patients were taking ß-blockers (2), calcium
channel antagonists (5), and
angiotensin-converting enzyme inhibitors
(1). In the UA group, patients were taking ß-blockers (5),
calcium channel antagonists (11), oral nitrates (10), and
angiotensin-converting enzyme inhibitors
(3). No effect due to preexisting medication was detected.
|
P-selectin was expressed on 2.5% (1.4% to 6.3%) of the platelets
in the AMI group, 2.3% (1.6% to 3.3%) in the UA group, and 1.0%
(0.6% to 1.9%) in control subjects (P<.001 for AMI and UA
versus control subjects) (Fig 2). GPIIb/IIIa expression
(in arbitrary units of mean fluorescence) was 101.6±2.7 in
AMI, 100.2±3.3 in UA, and 87.8±2.5 in control subjects
(P=.002 for AMI and P=.006 for UA versus
control
subjects). There was no significant difference between AMI and UA for
either P-selectin or GPIIb/IIIa expression. No differences were
detected due to time from onset of AMI or duration of UA. In AMI
patients receiving GTN, the median (range) fall in the percentage of
platelets expressing P-selectin was 0.5% (-0.2% to 1.9%),
P-selectin expression falling from 2.1% (1.4% to 6.3%) to 1.5%
(0.6% to 6.5%) (P=.013) (Fig 3). In those
AMI patients receiving GSNO, the median fall in P-selectin was 1.1%
(0.3% to 2.0%), the median falling from 2.7% (1.9% to 5.8%) to
1.7% (0.5% to 5.6%) (P=.005). In UA patients given GTN,
the median fall in P-selectin was 0.9% (0.3% to 1.9%), from 2.1%
(1.7% to 2.7%) to 1.2% (0.9% to 1.7%) (P=.005) (Fig
4); in those given GSNO, the median fall in P-selectin
was 1.2% (0.3% to 2.0%), from 2.5% (1.8% to 3.3%) to 1.1% (0.7%
to 2.0%) (P=.005). GPIIb/IIIa mean fluorescence
fell 7.2 (0 to 15.5) (P=.008) in AMI patients receiving GTN,
4.8 (-3.9 to 17.7) (P<.05) in AMI patients receiving
GSNO, 7.1 (0 to 16.6) (P=.008) in UA patients receiving GTN,
and 10.3 (0 to 17.1) (P=.012) in UA patients receiving GSNO
(Fig 5). Comparison between the decreases in P-selectin
and GPIIb/IIIa expression after treatment with GTN or GSNO showed no
significant difference.
|
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
These data demonstrate systemic platelet activation, despite aspirin treatment, in patients with AMI and UA. There were no significant differences between AMI and UA patients. A difference in bleeding time has been found between AMI and UA subjects,20 but other parameters of platelet activation are increased in both.4 5 6 7 11 Differences in outcomes of studies of UA may relate to the heterogeneity of the groups studied (ie, according to different definitions of UA),19 so in this study only the most acute cases were included. In AMI platelet activation may be increased by thrombolysis,21 but studies in patients without thrombolysis also demonstrate platelet activation, suggesting that thrombolysis is not the cause.4 20 Indeed, the platelet activation seen in AMI may precede the acute event, since megakaryocyte size is increased in AMI and sudden death,22 and increased platelet volume (larger platelets being more active) carries an increased risk of death and second infarct following first MI.23 In addition, increased systemic platelet activation in apparently healthy patients or those with stable angina predicts future acute events.24 25 Thus, although the thrombosis is a local problem in AMI and UA, there is generalized platelet activation that may be an important causative and prognostic factor. The greater number of smokers among our AMI and UA patients may have increased the median platelet activation,26 although the effect of smoking would have been reduced due to cessation on admission to hospital27 ; we did not detect any significant difference between smokers and nonsmokers in our patient groups.
The percentage of platelets expressing P-selectin in UA patients in this study was less than that found previously,7 as was P-selectin expression in normal control subjects.7 28 There is no standardization between laboratories in collection and processing of flow cytometry samples, so variation between studies may be due to differences in techniques that cause varying amounts of in vitro activation.28 Fixation of platelets with formaldehyde increases P-selectin expression,29 as does longer incubation time with the fluorescent antibody.30 We used whole blood that was carefully obtained (ie, with minimal tourniquet use), did not fix platelets, and processed samples immediately to minimize artifactual platelet activation. Incubation time was limited to 5 minutes to optimize detection of short-lasting NO effects. Studies also vary in how they define positivity. Our definition of positivity for P-selectin, FITC fluorescence >99% of platelets incubated with the nonspecific antibody, gives a greater specificity than the lower thresholds used in some studies.
Aspirin is only partially effective in treating both AMI and
UA.9 10 Our results demonstrate that platelet
activation persists despite standard aspirin treatment. The increased
platelet P-selectin expression in aspirin-treated patients is
consistent with the failure of aspirin to inhibit ADP-induced
platelet -granule release.31 Since continuing
platelet activation is associated with an adverse
prognosis,5 8 this suggests that additional
anti-platelet therapy is necessary. NO is a potent
anti-platelet agent, inhibiting not only aggregation but also,
unlike aspirin, adhesion. In contrast to the effects of aspirin on
cyclic AMP, NO increases platelet cyclic GMP, inhibiting
-granule release as well as activation of
GPIIb/IIIa.32 However, it has been unclear whether GTN
exerts a measurable effect on platelets in vivo at
hemodynamically tolerated doses.14 33 The
reason earlier studies did not demonstrate an anti-platelet
effect of GTN is probably due to the methods used, which resulted in
delays in performing platelet studies. Since the biological effect
of NO has a short half-life, immediate analysis is
necessary. An effect has been demonstrated by using bedside
aggregometry.15 In addition, the platelet effects of
NO donors may be more pronounced in the presence of
aspirin.34 By using flow cytometry we were able to
analyze the platelets immediately, thus optimizing the
detection of NO effects; unlike the results of aggregometry, the
present results were not invalidated by the presence of
aspirin.
We found that platelet activation in these patients was inhibited by both GTN and GSNO. The effect with GSNO was slightly greater, but this was not statistically significant for any of the parameters tested. At the doses required for this platelet inhibition GSNO was well tolerated, whereas in 2 patients treated with GTN the mean arterial pressure fell by more than 10 mm Hg with the starting dose. one other patient was unable to tolerate the initial 15-minute infusion due to headache. A relatively platelet-specific effect of GSNO has been demonstrated,16 17 18 and this study confirms that a significant systemic anti-platelet effect can be obtained without causing hypotension. There is evidence of a beneficial effect of GTN on coronary artery patency and left ventricular function following AMI,35 36 and it is useful in the treatment of UA.37 A review of trials of intravenous nitrates in MI suggests a reduction in mortality with nitroglycerin and nitroprusside.38 However, in the GISSI-3 and ISIS-4 trials there were no significant benefits with nitrate therapy.39 40 The lack of a significant effect may be related to the fact that over 50% of patients in the control groups also received nitrate therapy, including intravenous GTN. Isosorbide mononitrate, which was used in ISIS-4, is a relatively weak anti-platelet agent,41 and the regimen used is unlikely to be as effective as the doses of NO donors used in our study.
Platelet activation is important in the pathogenesis of AMI and UA, and continuing platelet activation is associated with an adverse outcome. We have demonstrated that platelet activation that continues despite aspirin treatment is inhibited by NO donors. This suggests that the use of NO donors, particularly more platelet-specific agents such as GSNO, may be useful adjuncts to conventional anti-platelet treatment in AMI and UA patients. Future studies should include platelet-specific NO donors to evaluate their use.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
Dr Langford is a Medical Research Council Training Fellow; Dr Martin is a British Heart Foundation Professor of Cardiovascular Science.
Received August 17, 1995; accepted September 22, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J. 1985;53:363-373.
2.
Falk E. Unstable angina with fatal outcome:
dynamic coronary thrombosis leading to infarction and/or sudden
death. Circulation. 1985;71:699-708.
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. Smitherman TC, Milam M, Woo J, Willerson JT, Frenkel EP. Elevated beta thromboglobulin in peripheral venous blood of patients with acute myocardial ischaemia: direct evidence for enhanced platelet reactivity in vivo. Am J Cardiol. 1981;48:395-402. [Medline] [Order article via Infotrieve]
5. Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med. 1986;315:983-989. [Abstract]
6. Gray RP, Hendra TJ, Patterson DLH, Yudkin JS. Spontaneous platelet aggregation in whole blood in diabetic and non-diabetic survivors of acute myocardial infarction. Thromb Haemost. 1993;70:932-936. [Medline] [Order article via Infotrieve]
7. Becker RC, Tracey RP, Bovill EG, Mann KG, Ault K. The clinical use of flow cytometry for assessing platelet activation in acute coronary syndromes. Coron Artery Dis. 1994;5:339-345. [Medline] [Order article via Infotrieve]
8. Trip MD, Cats VM, van Capelle FJL, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990;322:1549-1554. [Abstract]
9. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-360. [Medline] [Order article via Infotrieve]
10. Lewis HD, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med. 1983;309:396-403. [Abstract]
11. Giles H, Smith REA, Martin JF. Platelet glycoprotein IIb-IIIa and size are increased in acute myocardial infarction. Eur J Clin Invest. 1994;24:69-72. [Medline] [Order article via Infotrieve]
12.
Radomski MW, Palmer RMJ, Moncada S. An
L-arginine/nitric oxide pathway present in human platelets
regulates aggregation. Proc Natl Acad Sci U S A. 1990;87:5193-5197.
13. Radomski MW, Palmer RMJ, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;2:1057-1058. [Medline] [Order article via Infotrieve]
14. Mehta J, Mehta P. Comparative effect of nitroprusside and nitroglycerin on platelet aggregation in patients with heart failure. J Cardiovasc Pharmacol. 1980;2:25-33. [Medline] [Order article via Infotrieve]
15. Diodati J, Theroux P, Latour J-G, Lacoste L, Lam JYT, Waters D. Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina pectoris and acute myocardial infarction. Am J Cardiol. 1990;66:683-688. [Medline] [Order article via Infotrieve]
16. Radomski MW, Rees DD, Dutra A, Moncada S. S-nitroso-glutathione inhibits platelet activation in vitro and in vivo. Br J Pharmacol. 1992;107:745-749. [Medline] [Order article via Infotrieve]
17. de Belder AJ, MacAllister R, Radomski MW, Moncada S, Vallance PJT. Effects of S-nitroso-glutathione in the human forearm circulation: evidence for selective inhibition of platelet activation. Cardiovasc Res. 1994;28:691-694. [Medline] [Order article via Infotrieve]
18. Langford EJ, Brown AS, Wainwright RJ, de Belder AJ, Thomas MR, Smith REA, Radomski MW, Martin JF, Moncada S. Inhibition of platelet activity by S-nitrosoglutathione during coronary angioplasty. Lancet. 1994;344:1458-1460. [Medline] [Order article via Infotrieve]
19.
Braunwald E. Unstable angina: a
classification. Circulation. 1989;80:410-414.
20.
Kristensen SD, Bath PMW, Martin JF. Differences
in bleeding time, aspirin sensitivity and adrenaline between acute
myocardial infarction and unstable angina. Cardiovasc
Res. 1990;24:19-23.
21.
Fitzgerald DJ, Catella F, Roy L, Fitzgerald GA.
Marked platelet activation in vivo after intravenous
streptokinase in patients with acute myocardial infarction.
Circulation. 1988;77:142-150.
22. Trowbridge EA, Slater DN, Kishk YT, Woodcock BW, Martin JF. Platelet production in myocardial infarction and sudden cardiac death. Thromb Haemost. 1984;52:167-171. [Medline] [Order article via Infotrieve]
23. Martin JF, Bath PMW, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet. 1991;338:1409-1411. [Medline] [Order article via Infotrieve]
24.
Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn
PF. Blood platelet count and function are related to total
and cardiovascular death in apparently healthy
men. Circulation. 1991;84:613-617.
25. Lam JYT, Latour J-G, Lesperance J, Waters D. Platelet aggregation, coronary artery disease progression and future coronary events. Am J Cardiol. 1994;73:333-338. [Medline] [Order article via Infotrieve]
26. Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol. 1993;22:1168-1169. [Medline] [Order article via Infotrieve]
27. Terres W, Becker P, Rosenberg A. Changes in cardiovascular risk profile during cessation of smoking. Am J Med. 1994;97:242-249. [Medline] [Order article via Infotrieve]
28. Jackson CW. Role and evaluation of megakaryocytes and platelets in cardiovascular disease: a meeting perspective. Eur J Clin Invest. 1994;24:100-104. [Medline] [Order article via Infotrieve]
29. Cahill MR, Macey MG, Newland AC. Fixation with formaldehyde induces expression of activation dependent platelet membrane glycoproteins P-selectin (CD62) and GP53 (CD63). Br J Haematol. 1993;84:527-529. [Medline] [Order article via Infotrieve]
30. Janes SL, Wilson DJ, Cox AD, Chronos NAF, Goodall AH. ADP causes partial degranulation of platelets in the absence of aggregation. Br J Haematol. 1994;86:568-573. [Medline] [Order article via Infotrieve]
31.
Rinder CS, Student LA, Bonan JL, Rinder HM, Smith
BR. Aspirin does not inhibit adenosine
diphosphate-induced platelet -granule release.
Blood. 1993;82:505-512.
32. Horstrup K, Jablonka B, Honig-Liedl P, Just M, Kochsiek K, Walter U. Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser 157 in intact human platelets correlates with fibrinogen receptor inhibition. Eur J Biochem. 1994;225:21-27. [Medline] [Order article via Infotrieve]
33.
Fitzgerald DJ, Roy L, Robertson RM, Fitzgerald
GA. The effects of organic nitrates on prostacyclin biosynthesis
and platelet function in humans.
Circulation. 1984;70:297-302.
34. Cockcroft JR, Ritter JM. Effects of aspirin and glyceryl trinitrate on bleeding time in man. Thromb Haemorrh Disorders. 1991;3:49-51.
35.
Jugdutt BI, Sussex BA, Warnica JW, Rossall RE.
Persistent reduction in left ventricular asynergy in
patients with acute myocardial infarction by intravenous
infusion of nitroglycerin.
Circulation. 1983;68:1264-1273.
36. 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]
37. Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M. Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. Am J Cardiol. 1983;51:694-698. [Medline] [Order article via Infotrieve]
38. Yusuf S, Collins R, MacMahon S, Peto R. Effect of intravenous nitrates on mortality in acute myocardial infarction: an overview of the randomised trials. Lancet.. 1988;1:1088-1092. [Medline] [Order article via Infotrieve]
39. GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza Nell'infarto Miocardico). GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet.. 1994;343:1115-1122. [Medline] [Order article via Infotrieve]
40. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet.. 1995;345:669-685. [Medline] [Order article via Infotrieve]
41. Gerzer R, Karrenbrock B, Siess W, Heim J-M. Direct comparison of the effects of nitroprusside, SIN-1, and various nitrates on platelet aggregation and soluble guanylate cyclase activity. Thromb Res. 1988;52:11-21.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  G. Vilahur, E. Segales, E. Salas, and L. Badimon Effects of a Novel Platelet Nitric Oxide Donor (LA816), Aspirin, Clopidogrel, and Combined Therapy in Inhibiting Flow- and Lesion-Dependent Thrombosis in the Porcine Ex Vivo Model Circulation, September 21, 2004; 110(12): 1686 - 1693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Kaposzta, A. Clifton, J. Molloy, J. F. Martin, and H. S. Markus S-Nitrosoglutathione Reduces Asymptomatic Embolization After Carotid Angioplasty Circulation, December 10, 2002; 106(24): 3057 - 3062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mirabet, D. Garcia-Dorado, J. Inserte, J. A. Barrabes, R.-M. Lidon, B. Soriano, M. Azevedo, F. Padilla, L. Agullo, M. Ruiz-Meana, et al. Platelets activated by transient coronary occlusion exacerbate ischemia-reperfusion injury in rat hearts Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1134 - H1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Sanchez de Miguel, M. a M. Arriero, J. Farre, P. Jimenez, A. Garcia-Mendez, T. de Frutos, A. Jimenez, R. Garcia, F. Cabestrero, J. Gomez, et al. Nitric oxide production by neutrophils obtained from patients during acute coronary syndromes: expression of the nitric oxide synthase isoforms J. Am. Coll. Cardiol., March 6, 2002; 39(5): 818 - 825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T O'malley, C.A Ludlam, R.A Riemermsa, and K.A.A Fox Early increase in levels of soluble inter-cellular adhesion molecule-1 (sICAM-1). Potential risk factor for the acute coronary syndromes Eur. Heart J., July 2, 2001; 22(14): 1226 - 1234. [Abstract] [PDF]
|
|
|
|
|
|
Z. Kaposzta, P. A. Baskerville, D. Madge, S. Fraser, J. F. Martin, and H. S. Markus L-Arginine and S-Nitrosoglutathione Reduce Embolization in Humans Circulation, May 15, 2001; 103(19): 2371 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V. Lewis, A. M. Dart, and J. P. F. Chin-Dusting Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol J. Am. Coll. Cardiol., March 1, 1999; 33(3): 805 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Markovitz, L. Tolbert, and S. E. Winders Increased Serotonin Receptor Density and Platelet GPIIb/IIIa Activation Among Smokers Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 762 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Minamino, M. Kitakaze, S. Sanada, H. Asanuama, T. Kurotobi, Y. Koretsune, M. Fukunami, T. Kuzuya, N. Hoki, and M. Hori Increased Expression of P-Selectin on Platelets Is a Risk Factor for Silent Cerebral Infarction in Patients With Atrial Fibrillation : Role of Nitric Oxide Circulation, October 27, 1998; 98(17): 1721 - 1727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Molloy, J. F. Martin, P. A. Baskerville, S. C. A. Fraser, and H. S. Markus S-Nitrosoglutathione Reduces the Rate of Embolization in Humans Circulation, October 6, 1998; 98(14): 1372 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Skinner, C. R. White, R. Patel, S. Tan, S. Barnes, M. Kirk, V. Darley-Usmar, and D. A. Parks Nitrosation of Uric Acid by Peroxynitrite. FORMATION OF A VASOACTIVE NITRIC OXIDE DONOR J. Biol. Chem., September 18, 1998; 273(38): 24491 - 24497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Salas, E J Langford, M T Marrinan, J F Martin, S Moncada, and A J de Belder S-Nitrosoglutathione inhibits platelet activation and deposition in coronary artery saphenous vein grafts in vitro and in vivo Heart, August 1, 1998; 80(2): 146 - 150. [Abstract] [Full Text]
|
|
|
|
|
|
A. Gries, C. Bode, K. Peter, A. Herr, H. Bohrer, J. Motsch, and E. Martin Inhaled Nitric Oxide Inhibits Human Platelet Aggregation, P-Selectin Expression, and Fibrinogen Binding In Vitro and In Vivo Circulation, April 21, 1998; 97(15): 1481 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Provost, J. Tremblay, and Y. Merhi The Antiadhesive and Antithrombotic Effects of the Nitric Oxide Donor SIN-1 Are Combined With a Decreased Vasoconstriction in a Porcine Model of Balloon Angioplasty Arterioscler Thromb Vasc Biol, September 1, 1997; 17(9): 1806 - 1812. [Abstract] [Full Text]
|
|
|
|
|
|
Z. Kaposzta, J. F. Martin, and H. S. Markus Switching off Embolization From Symptomatic Carotid Plaque Using S-Nitrosoglutathione Circulation, March 26, 2002; 105(12): 1480 - 1484. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||