From the Departments of Pharmacology and Medicine, Georgetown University
Medical Center, Washington, DC (J.E.F.), and the Whitaker Cardiovascular
Institute and Evans Department of Medicine, Boston University School of
Medicine, Boston, Mass (B.T., B.H., J.L., J.F.K., J.A.V.).
Correspondence to Dr Jane E. Freedman, Med-Dent Bldg Room NE 403, Georgetown University Medical Center, 3900 Reservoir Rd, NW, Washington, DC 20007. E-mail: Freedmaj{at}gunet.georgetown.edu
Background—Thrombus formation
within a coronary vessel is the acute precipitating event in
most acute coronary syndromes. Recently, constitutive nitric
oxide synthase (cNOS) has been identified in human platelets, and
platelet-derived nitric oxide has been shown to inhibit
platelet recruitment after aggregation. However, its role in
regulating platelet responses under normal or pathologic conditions
has not yet been elucidated.
Methods and Results—We examined nitric oxide (NO)
production by platelets isolated from 87 patients
undergoing coronary angiography, 37 with stable angina and 50
with unstable angina or a myocardial infarction within 2 weeks. After
stimulation with 5 µmol/L ADP, platelet aggregation and NO
production were simultaneously measured with an
NO-selective microelectrode adapted for use in a standard platelet
aggregometer. Mean (±SEM) platelet-derived NO production
was 1.78±0.36 pmol/108 and 0.26±0.05 pmol/108
platelets in coronary patients with stable angina and acute
coronary syndromes, respectively (P=0.0001). By
logistic regression analysis, heparin treatment (odds ratio
6.6, CI 1.9 to 22.8, P=0.003), lower platelet-NO
production (odds ratio 4.0, CI 1.3 to 11.5,
P=0.01), and extent of atherosclerosis
(odds ratio 1.5, CI 1.1 to 2.0, P=0.02) were independent
predictors of an acute coronary syndrome. In the subset of
patients with angiographic evidence of atherosclerosis
(n=83), logistic regression demonstrated that platelet NO
production (odds ratio 3.9, CI 1.3 to 11.1,
P=0.01) and heparin treatment (odds ratio 6.4, CI 1.9 to
22.0, P=0.004) were independent predictors of an acute
coronary syndrome, whereas extent of
atherosclerosis was not.
Conclusions—In summary, aggregating platelets from patients
with acute coronary syndromes produce less NO. Since
platelet aggregation and thrombus formation are implicated in
unstable angina and myocardial infarction, impaired
platelet-derived NO production may contribute to the
development of acute coronary syndromes.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Impaired Platelet Production of Nitric Oxide Predicts Presence of Acute Coronary Syndromes
Key Words: platelets • nitric oxide • thrombosis • coronary disease
This article has been cited by other articles:
 |
|
 |
|
  P. O'Kane, L. Xie, Z. Liu, L. Queen, G. Jackson, Y. Ji, and A. Ferro Aspirin acetylates nitric oxide synthase type 3 in platelets thereby increasing its activity Cardiovasc Res, July 1, 2009; 83(1): 123 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Freedman Oxidative Stress and Platelets Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): s11 - s16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Gkaliagkousi, J. Ritter, and A. Ferro Platelet-Derived Nitric Oxide Signaling and Regulation Circ. Res., September 28, 2007; 101(7): 654 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M.C. Brunini, A. C. Mendes-Ribeiro, J. C. Ellory, and G. E. Mann Platelet nitric oxide synthesis in uremia and malnutrition: A role for L-arginine supplementation in vascular protection? Cardiovasc Res, January 15, 2007; 73(2): 359 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shimasaki, Y. Saito, M. Yoshimura, S. Kamitani, Y. Miyamoto, I. Masuda, M. Nakayama, Y. Mizuno, H. Ogawa, H. Yasue, et al. The Effects of Long-term Smoking on Endothelial Nitric Oxide Synthase mRNA Expression in Human Platelets as Detected With Real-time Quantitative RT-PCR Clinical and Applied Thrombosis/Hemostasis, January 1, 2007; 13(1): 43 - 51. [Abstract] [PDF]
|
|
|
|
|
|
S. R. Willoughby, S. Stewart, A. S. Holmes, Y. Y. Chirkov, and J. D. Horowitz Platelet Nitric Oxide Responsiveness: A Novel Prognostic Marker in Acute Coronary Syndromes Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2661 - 2666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Freedman Molecular Regulation of Platelet-Dependent Thrombosis Circulation, October 25, 2005; 112(17): 2725 - 2734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Mollace, C. Muscoli, E. Masini, S. Cuzzocrea, and D. Salvemini Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors Pharmacol. Rev., June 1, 2005; 57(2): 217 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Morita, H. Ikeda, N. Haramaki, H. Eguchi, and T. Imaizumi Only two-week smoking cessation improves platelet aggregability and intraplatelet redox imbalance of long-term smokers J. Am. Coll. Cardiol., February 15, 2005; 45(4): 589 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 S. Fichtlscherer, S. Breuer, V. Schachinger, S. Dimmeler, and A. M. Zeiher C-reactive protein levels determine systemic nitric oxide bioavailability in patients with coronary artery disease Eur. Heart J., August 2, 2004; 25(16): 1412 - 1418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Landmesser, B. Hornig, and H. Drexler Endothelial Function: A Critical Determinant in Atherosclerosis? Circulation, June 1, 2004; 109(21_suppl_1): II-27 - II-33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rajagopalan, E. C. Somers, R. D. Brook, C. Kehrer, D. Pfenninger, E. Lewis, A. Chakrabarti, B. C. Richardson, E. Shelden, W. J. McCune, et al. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity Blood, May 15, 2004; 103(10): 3677 - 3683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Vilahur, M. I. Baldellou, E. Segales, E. Salas, and L. Badimon Inhibition of thrombosis by a novel platelet selective S-nitrosothiol compound without hemodynamic side effects Cardiovasc Res, March 1, 2004; 61(4): 806 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Heitzer, I. Ollmann, K. Koke, T. Meinertz, and T. Munzel Platelet Glycoprotein IIb/IIIa Receptor Blockade Improves Vascular Nitric Oxide Bioavailability in Patients With Coronary Artery Disease Circulation, August 5, 2003; 108(5): 536 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. D. O'Kane, L. R. Queen, Y. Ji, V. Reebye, P. Stratton, G. Jackson, and A. Ferro Aspirin modifies nitric oxide synthase activity in platelets: effects of acute versus chronic aspirin treatment Cardiovasc Res, July 1, 2003; 59(1): 152 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Gorchakova, W. Koch, N. von Beckerath, J. Mehilli, A. Schomig, and A. Kastrati Association of a genetic variant of endothelial nitric oxide synthase with the 1 year clinical outcome after coronary stent placement Eur. Heart J., May 1, 2003; 24(9): 820 - 827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Shishehbor, R. J. Aviles, M.-L. Brennan, X. Fu, M. Goormastic, G. L. Pearce, N. Gokce, J. F. Keaney Jr, M. S. Penn, D. L. Sprecher, et al. Association of Nitrotyrosine Levels With Cardiovascular Disease and Modulation by Statin Therapy JAMA, April 2, 2003; 289(13): 1675 - 1680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Liu, A. Wallmon, C. Olsson-Mortlock, R. Wallin, and T. Saldeen Mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms Am. J. Clinical Nutrition, March 1, 2003; 77(3): 700 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Cominacini, A. Fratta Pasini, U. Garbin, A. Pastorino, A. Rigoni, C. Nava, A. Davoli, V. Lo Cascio, and T. Sawamura The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells J. Am. Coll. Cardiol., February 5, 2003; 41(3): 499 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kanaya, H. Ikeda, N. Haramaki, T. Murohara, and T. Imaizumi Intraplatelet Tetrahydrobiopterin Plays an Important Role in Regulating Canine Coronary Arterial Thrombosis by Modulating Intraplatelet Nitric Oxide and Superoxide Generation Circulation, November 13, 2001; 104(20): 2478 - 2484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Takajo, H. Ikeda, N. Haramaki, T. Murohara, and T. Imaizumi Augmented oxidative stress of platelets in chronic smokers: Mechanisms of impaired platelet-derived nitric oxide bioactivity and augmented platelet aggregability J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1320 - 1327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Huang, H. Xiao, J. M. Samii, J. A. Vita, and J. F. Keaney Jr. Contrasting effects of thiol-modulating agents on endothelial NO bioactivity Am J Physiol Cell Physiol, August 1, 2001; 281(2): C719 - C725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Freedman, C. Parker III, L. Li, J. A. Perlman, B. Frei, V. Ivanov, L. R. Deak, M. D. Iafrati, and J. D. Folts Select Flavonoids and Whole Juice From Purple Grapes Inhibit Platelet Function and Enhance Nitric Oxide Release Circulation, June 12, 2001; 103(23): 2792 - 2798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Li, T. Saldeen, F. Romeo, and J. L. Mehta Different Isoforms of Tocopherols Enhance Nitric Oxide Synthase Phosphorylation and Inhibit Human Platelet Aggregation and Lipid Peroxidation: Implications in Therapy with Vitamin E Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2001; 6(2): 155 - 161. [Abstract] [PDF]
|
|
|
|
|
|
S. J. Duffy, J. A. Vita, M. Holbrook, P. L. Swerdloff, and J. F. Keaney Jr Effect of Acute and Chronic Tea Consumption on Platelet Aggregation in Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 1084 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Loscalzo Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis Circ. Res., April 27, 2001; 88(8): 756 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.C. Mendes Ribeiro, T.M.C. Brunini, J.C. Ellory, and G.E. Mann Abnormalities in L-arginine transport and nitric oxide biosynthesis in chronic renal and heart failure Cardiovasc Res, March 1, 2001; 49(4): 697 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Tousoulis, C Tentolouris, T Crake, G Goumas, C Stefanadis, P Toutouzas, and G Davies Complex stenosis morphology and vasomotor responses to inhibition of nitric oxide synthesis Heart, November 1, 2000; 84(5): 529 - 534. [Abstract] [Full Text]
|
|
|
|
 |
|
 U. Laufs, K. Gertz, P. Huang, G. Nickenig, M. Bohm, U. Dirnagl, M. Endres, and C. J. Vaughan Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice Editorial Comment Stroke, October 1, 2000; 31(10): 2442 - 2449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. Queen, B. Xu, K. Horinouchi, I. Fisher, and A. Ferro {beta}2-Adrenoceptors Activate Nitric Oxide Synthase in Human Platelets Circ. Res., July 7, 2000; 87(1): 39 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yang and J. Loscalzo Regulation of Tissue Factor Expression in Human Microvascular Endothelial Cells by Nitric Oxide Circulation, May 9, 2000; 101(18): 2144 - 2148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Anderson Assessment and treatment of endothelial dysfunction in humans J. Am. Coll. Cardiol., September 1, 1999; 34(3): 631 - 638. [Full Text] [PDF]
|
|
|
|
|
|
C. S Hayward, R. P Kelly, and P. S Macdonald Inhaled nitric oxide in cardiology practice Cardiovasc Res, August 15, 1999; 43(3): 628 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Freedman, R. Sauter, E. M. Battinelli, K. Ault, C. Knowles, P. L. Huang, and J. Loscalzo Deficient Platelet-Derived Nitric Oxide and Enhanced Hemostasis in Mice Lacking the NOSIII Gene Circ. Res., June 25, 1999; 84(12): 1416 - 1421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Huang, J. A. Vita, R. C. Venema, and J. F. Keaney Jr. Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intracellular Tetrahydrobiopterin J. Biol. Chem., June 2, 2000; 275(23): 17399 - 17406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Yan and J. W. Smith A Redox Site Involved in Integrin Activation J. Biol. Chem., December 15, 2000; 275(51): 39964 - 39972. [Abstract] [Full Text] [PDF]
|
|