Glycoprotein IIb/IIIa inhibition enhances platelet nitric oxide release

Chakrabarti, Subrata; Clutton, Patricia; Varghese, Sonia; Cox, Dermot; Mascelli, Mary Ann; Freedman, Jane E.

doi:10.1016/j.thromres.2004.02.018

Cited by 25 publications

(20 citation statements)

References 29 publications

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“…50 There is accumulating evidence that platelet-derived O 2 Ϫ is a functionally relevant scavenger of platelet-derived NO, which inhibits the anti-aggregatory effects of platelet-derived NO. 45,61 In accordance with this, GPIIb/IIIa inhibitors decrease platelet O 2 Ϫ release and enhance platelet NO release concomitantly. 61 Some of these observations also indicate that an effect of plateletderived ROS on platelet aggregation may play a prominent role in a late phase of aggregation.…”

Section: Role Of Ros In Platelet Signalingsupporting

confidence: 56%

Reactive Oxygen Species

Krötz

Sohn

Pohl

2004

ATVB

405

122

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Abstract-Platelets participate not only in thrombus formation but also in the regulation of vessel tone, the development of atherosclerosis, angiogenesis, and in neointima formation after vessel wall injury. It is not surprising, therefore, that the platelet activation cascade (including receptor-mediated tethering to the endothelium, rolling, firm adhesion, aggregation, and thrombus formation) is tightly regulated. In addition to already well-defined platelet regulatory factors, such as nitric oxide (NO), prostacyclin (PGI 2 ), and adenosine, reactive oxygen species (ROS) participate in the regulation of platelet activation. Although exogenously derived ROS are known to affect the regulation of platelet activation, recent data suggest that the platelets themselves generate ROS. Intracellular ROS signaling in activated platelets could be of significant relevance after transient platelet contact with the vessel wall, during the recruitment of additional platelets, and in thrombus formation. This review discusses the potential cellular and enzymatic sources of ROS in platelets, their molecular mechanisms of action in platelet activation, and summarizes in vitro and in vivo evidence for their physiological and potential therapeutic relevance. Key Words: platelets Ⅲ reactive oxygen species Ⅲ NAD(P)H-oxidase Ⅲ aggregation Ⅲ adhesion Ⅲ thrombus formation P latelet interaction with the vessel wall serves numerous physiological and pathophysiological functions. This is reflected by the fact that platelets release growth factors, 1 lipid mediators, 2,3 and cytokines. 4 Consequently, the regulation of platelet activity plays a role not only for thrombus formation and the regulation of vascular tone 5 but also for the vascular pathophysiology of angiogenesis and inflammation. Moreover, platelets participate in the development of atherothrombotic disease by promoting atherosclerotic lesion 6 and neointima formation. 7 Not surprisingly, the activation of platelets is regulated and modulated by numerous factors, blood-borne and cell-derived. Most of these factors are relatively well-characterized. 8 However, in recent time, several publications have suggested that reactive oxygen species (ROS) represent a new modulator of platelet activity. It has been known for some time that ROS exert critical regulatory functions within the vascular wall and it is therefore plausible that platelets represent a relevant target for their action.Within the vessel wall (where endothelial cells, vascular smooth muscle cells, and fibroblasts express a variety of ROS-generating enzymes), there is a constant, low-quantity flux of ROS. It is already established that enhanced ROS release from the vascular wall can indirectly affect platelet activity by scavenging nitric oxide (NO), thereby decreasing the antiplatelet properties of the endothelium. 9 In addition to their exposure to ROS derived from the vascular wall, platelets themselves also can generate ROS, and there is some evidence for a more direct role of ROS in the control of platelet activi...

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Section: Role Of Ros In Platelet Signalingsupporting

confidence: 56%

Reactive Oxygen Species

Krötz

Sohn

Pohl

2004

ATVB

405

122

View full text Add to dashboard Cite

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“…Interestingly, a recent study demonstrated that glycoprotein IIb/IIIa inhibition both decreases platelet superoxide release and enhances platelet NO production. 28 Whether clopidogrel has similar intrinsic activating properties remains to be investigated. Our finding of increased NOx plasma levels in patients after chronic clopidogrel treatment is well in line with the observed reduced oxidative stress and improved systemic endothelial NO bioavailability.…”

Section: Discussionmentioning

confidence: 99%

Clopidogrel Improves Systemic Endothelial Nitric Oxide Bioavailability in Patients With Coronary Artery Disease

Heitzer

Rudolph

Schwedhelm

et al. 2006

ATVB

131

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Background-Platelet stimulation and activation are known not only as prerequisite of clot formation but are increasingly recognized as important contributors to inflammation and vascular injury. The present study in patients with symptomatic coronary disease investigated whether platelet adenosine diphosphate receptor blockade by clopidogrel exerts beneficial effects on endothelial nitric oxide bioavailability, oxidative stress, and/or inflammatory status. Methods and Results-One hundred three consecutive patients with symptomatic coronary disease and long-term aspirin therapy were studied. Endothelium-dependent and -independent vasodilation was determined measuring forearm blood flow (FBF)-responses to acetylcholine with and without N G -monomethyl-L-arginin (L-NMMA) and sodium nitroprusside, by using venous occlusion plethysmography. Patients were randomized to receive additional treatment with clopidogrel or placebo. Vascular function tests were repeated after 5 weeks and showed significant improvement of acetylcholine-induced vasodilatation and L-NMMA responses in the clopidogrel-added group (max. FBF from 9.8Ϯ0.3 to 14.7Ϯ0.4; L-NMMA-response from 3.7Ϯ0.1 to 6.8Ϯ0.3 mL/100 mL/min). In contrast, no significant changes were observed in the placebo group. Sodium nitroprusside-induced vasodilation was not changed in either group. Urinary excretion of 8-iso-prostaglandin F2␣ and plasma levels of hsCRP, sCD40L, and RANTES were reduced in patients on additional treatment with clopidogrel, but not in patients on placebo. Conclusions-Clopidogrel

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“…In a recent study, it was demonstrated that inhibition of the GPIIb/IIIa receptor, which is essential for fibrinogen binding and for a sustained platelet aggregation response, leads to an increase in platelet NO release and to attenuation of platelet O 2 Ϫ production on activation. 56 In another study, aspirin was found to activate platelet NOS3 acutely, while at the same time inhibiting ␤ 2 AR-mediated NOS3 activation. 57 Further work is needed to explore other therapeutic options for enhancing platelet NO release, and to investigate whether such therapies may be clinically useful.…”

Section: The L-arginine-no Pathway In Plateletsmentioning

confidence: 94%

Platelet-Derived Nitric Oxide Signaling and Regulation

Gkaliagkousi

Ritter

Ferro

2007

Circulation Research

140

103

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Abstract-Nitric oxide (NO) exerts important vasodilatory, antiplatelet, antioxidant, antiadhesive, and antiproliferative effects. Although endothelium derived NO has been shown to be of prime importance in cardio-and vasculoprotection, until recently little was known about the role of platelet-derived NO. New evidence suggests that NO synthesized by platelets regulates platelet functions, in particular suppressing platelet activation and intravascular thrombosis. Moreover, platelet NO biosynthesis may be decreased in patients with cardiovascular risk factors or with coronary heart disease, and this may contribute to arterial thrombotic disease in these patients. Here, we review the current state of knowledge as regards the role of platelet-derived NO, both in normal physiology and in cardiovascular disease states, and compare platelet NO signaling and regulation with that in endothelial cells. (Circ Res. 2007;101:654-662.)

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Glycoprotein IIb/IIIa inhibition enhances platelet nitric oxide release

Cited by 25 publications

References 29 publications

Reactive Oxygen Species

Reactive Oxygen Species

Clopidogrel Improves Systemic Endothelial Nitric Oxide Bioavailability in Patients With Coronary Artery Disease

Platelet-Derived Nitric Oxide Signaling and Regulation

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