Effects of nitric oxide/EDRF on platelet surface glycoproteins

Michelson, Alan D.; Benoit, Stephen E.; Furman, Mark I.; Breckwoldt, William L.; Rohrer, Michael J.; Barnard, Marc R.; Loscalzo, J.

doi:10.1152/ajpheart.1996.270.5.h1640

Cited by 76 publications

(71 citation statements)

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“…23 S-nitroso-Nacetyl-L-cysteine inhibits both thrombin-induced and U-46619 (a stable thromboxane A 2 analogue)-induced expression of platelet surface P selectin (a granule protein), CD63 (a lysosomal protein), and the calcium-dependent active conformation of the heterodimeric fibrinogen-binding integrin glycoprotein IIb/IIIa (␣ 2b /␤ 3 ). 24 This suppression of the conformational change in glycoprotein IIb/IIIa required for fibrinogen binding is associated with suppression of intracellular calcium flux and demonstrable reduction in both the affinity (2.7-fold increase in K d ) and number (50% decrease) of fibrinogen-binding sites on the platelet surface. 23 Inhibition of cytosolic calcium flux with exposure to strong platelet agonists like thrombin or U46619 seems to be a consequence of inhibition of capacitative calcium influx resulting from enhanced sarcoplasmic reticulum/endoplasmic reticulum calcium-ATPase-dependent refilling of calcium stores.…”

Section: In Vitro Studiesmentioning

confidence: 97%

Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis

Loscalzo

2001

Circulation Research

552

393

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Abstract-Nitric oxide (NO) was originally discovered as a vasodilator product of the endothelium. Over the last 15 years, this vascular mediator has been shown to have important antiplatelet actions as well. By activating guanylyl cyclase, inhibiting phosphoinositide 3-kinase, impairing capacitative calcium influx, and inhibiting cyclooxygenase-1, endothelial NO limits platelet activation, adhesion, and aggregation. Platelets are also an important source of NO, and this platelet-derived NO pool limits recruitment of platelets to the platelet-rich thrombus. A deficiency of bioactive NO is associated with arterial thrombosis in animal models, individuals with endothelial dysfunction, and patients with a deficiency of the extracellular antioxidant enzyme glutathione peroxidase-3. This enzyme catalyzes the reduction of hydrogen and lipid peroxides, which limits the availability of these reactive oxygen species to react with and inactivate NO. The complex biochemical reactions that underlie the function and inactivation of NO in the vasculature represent an important set of targets for therapeutic intervention for the prevention and treatment of arterial thrombotic disorders. Key Words: endothelium Ⅲ nitroglycerin Ⅲ S-nitrosothiols Ⅲ nitric oxide synthase Ⅲ oxidative stress N itrovasodilators have been used to alleviate myocardial ischemia for more than a century, and the recognition that they simulate endogenous endothelial nitric oxide (NO) represents one of the most important biological discoveries in cardiovascular biomedicine in the last 20 years. 1 Their antianginal effects have been mostly attributed to relaxation of vascular smooth muscle and resulting arterial vasodilation, which leads to improved perfusion and oxygen delivery. This class of drugs also manifests antithrombotic activity, principally by inhibiting platelet function. First shown by Hampton et al 2 in 1967, the antiplatelet effect of nitroglycerin remained controversial for many years because of the suprapharmacological doses required to inhibit platelet aggregation in vitro and the lack of evidence for a direct antiplatelet effect in vivo. Akin to its effects in vascular smooth muscle cells, 3,4 nitroglycerin also inhibits platelet aggregation by activating guanylyl cyclase, 5,6 and this inhibitory action can be potentiated by maintaining intracellular thiol redox state. 6 These observations, coupled with the recognition of the role of plateletdependent thrombus formation in acute coronary syndromes, led to renewed interest in the antiplatelet effects of nitrovasodilators and, eventually, of NO itself.In 1985, we reported the case of a 29-year-old woman with a hypertensive crisis treated with sodium nitroprusside for blood pressure control who sustained an intracerebral hemorrhage after being normotensive on therapy for 24 hours. 7 We showed that her bleeding time was prolonged, in vitro platelet aggregation was attenuated in the presence of N-acetyl-L-cysteine, and these abnormalities returned to normal with discontinuation of the sodium nitro...

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Section: In Vitro Studiesmentioning

confidence: 97%

Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis

Loscalzo

2001

Circulation Research

552

393

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“…Compared with strenuous exercise, moderate exercise induced lower levels of catecholamines and a higher release of nitric oxide (NO) from vascular endothelial cells [23]. Nitric oxide inhibits thrombus formation under high shear flow and attenuates agonistinduced upregulation of P-selectin and the GPIIb/ IIIa complex by negatively regulating the cGMP in platelets [39,40]. By increasing NO release, moderate exercise can decrease the performance of adhesion molecules on platelets, thereby reducing platelet activation induced by shear stress.…”

Section: Effects Of Acute Exercisementioning

confidence: 99%

Exercise prescription and thrombogenesis

Wang

2006

J Biomed Sci

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SummaryLifestyle habits, such as exercise, may significantly influence risk of major vascular thrombotic events. The risk of primary cardiac arrest has been shown to transiently increase during vigorous exercise, whereas regular moderate-intensity exercise is associated with an overall reduced risk of cardiovascular diseases. What are the mechanisms underlying these paradoxical effects of vigorous exercise versus exercise training on thrombotic modification? This review analyzes research regarding effects and their underlying mechanisms of acute exercise, endurance training, and deconditioning on platelets, coagulation, and fibrinolysis. Evidence suggests that (i) light, acute exercise ( £ 49% VO 2 max ) does not affect platelet reactivity and coagulation and increases fibrinolytic activity; (ii) moderate, acute exercise (50$74% VO 2max ) suppresses platelet reactivity and enhances fibrinolysis, which remains unchanged in the coagulation system; and, (iii) strenuous, acute exercise ( ‡ 75% VO 2max ) enhances both platelet reactivity and coagulation, simultaneously promoting fibrinolytic activity. Therefore, moderate exercise is likely a safe and effective exercise dosage for minimizing risk of cardiovascular diseases by inducing beneficial anti-thrombotic changes. Moreover, moderate-intensity exercise training reduces platelet reactivity and enhances fibrinolysis at rest, also attenuating enhanced platelet reactivity and augmenting hyper-fibrinolytic activity during strenuous exercise. However, these favorable effects of exercise training on thrombotic modification return to a pretraining state after a period of deconditioning. These findings can aid in determining appropriate exercise regimes to prevent early thrombotic events and further hinder the cardiovascular disease progression. Benefits and risks associated with exercise in cardiovascular diseasesIncreased physical activity [1] and cardiorespiratory fitness [2] are associated with a reduced risk of fatality from coronary heart disease, as well as other causes. Moreover, increased studies have demonstrated that regular moderate-intensity physical activity is associated with health benefits, even when aerobic fitness (e.g., maximal oxygen uptake, VO 2max ) remains unchanged [3] Conversely, clinical investigations conferred that strenuous, acute exercise can enhance risk of major vascular thrombotic events and transiently increase incidence of primary cardiac arrest [9,10]. The incidence of cardiovascular complications during exercise is substantially greater for those with cardiovascular disease than for healthy

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“…Nitric oxide also inhibits platelet aggregation (10,11) and prevents thrombosis in a model of endotoxin-induced glomerular damage (12). The normal activation-dependent increase in platelet surface glycoprotein expression, including P selectin and the activated glycoprotein IIb-IIIa complex (integrin ␣ IIb ␤ 3 ), is also inhibited by NO (13).…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide released from activated platelets inhibits platelet recruitment.

Freedman

Loscalzo²,

Barnard³

et al. 1997

J. Clin. Invest.

361

271

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Vessel injury and thrombus formation are the cause of most ischemic coronary syndromes and, in this setting, activated platelets stimulate platelet recruitment to the growing thrombus. Recently, a constitutive nitric oxide synthase (NOS) has been identified in human platelets. To further define the capacity of platelets to produce nitric oxide (NO), as well as to study the role of this NO in platelet recruitment, we adapted a NO-selective microelectrode for use in a standard platelet aggregometer, thereby permitting simultaneous measurement of platelet aggregation and NO production. Treatment of platelets with the NO synthase inhibitor L -N G -nitroarginine methyl ester (L-NAME), reduced NO production by 92 Ϯ 8% in response to 5 M ADP compared to control but increased aggregation by only 15 Ϯ 2%. In contrast, L-NAME had a more pronounced effect on platelet recruitment as evidenced by a 35 Ϯ 5% increase in the extent of aggregation, a 33 Ϯ 3% decrease in cyclic GMP content, and a 31 Ϯ 5% increase in serotonin release from a second recruitable population of platelets added to stimulated platelets at the peak of NO production. To study platelet recruitment accurately, we developed an assay that monitors two platelet populations simultaneously. Nonbiotinylated platelets were incubated with L-NAME or vehicle and activated with ADP. At peak NO production, biotinylated platelets were added. As measured by three-color flow cytometry, there was a 56 Ϯ 11% increase in the number of P selectinpositive platelets in the nonbiotinylated population treated with L-NAME as compared to control. When biotinylated platelets were added to the L-NAME-treated nonbiotinylated population, the number of P selectin positive biotinylated platelets increased by 180 Ϯ 32% as compared to biotinylated platelets added to the control. In summary, stimulated platelets produce NO that modestly inhibits platelet activation but markedly inhibits additional platelet recruitment. These data suggest that platelet-derived NO may regulate platelet re-

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Effects of nitric oxide/EDRF on platelet surface glycoproteins

Cited by 76 publications

References 0 publications

Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis

Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis

Exercise prescription and thrombogenesis

Nitric oxide released from activated platelets inhibits platelet recruitment.

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