Influence of glucose concentration on the effects of aspirin, ticlopidine and clopidogrel on platelet function and platelet–subendothelium interaction

Cruz, J. P. De La; Arrebola, María Monsalud; Villalobos, M.A.; Pinacho, Araceli; Guerrero, A.; Correa, José Antonio González; Cuesta, Felipe Sánchez de la

doi:10.1016/j.ejphar.2003.10.055

Cited by 21 publications

(16 citation statements)

References 37 publications

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“…The proaggregatory effects of hyperglycemia are also in part reversed by insulin. It has recently been shown [81], that high glucose concentrations decrease platelet NO production. Anti-aggregatory effects of insulin in vitro are partially mediated by incremental NO release from platelets [82], due to the activation of platelet NO synthase [83].…”

Section: Glycemic Controlmentioning

confidence: 99%

Platelet Hyperaggregability: Impaired Responsiveness to Nitric Oxide (“Platelet NO Resistance”) as a Therapeutic Target

Rajendran

Chirkov

2008

Cardiovasc Drugs Ther

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Platelet hyperaggregability and associated thrombosis have been documented in a number of cardiovascular disease states. While one of the current mainstays of anti-thrombotic treatment (i.e. aspirin, clopidogrel, glycoprotein IIb/IIIa antagonists) has been directed at reducing platelet activation and aggregation, it is apparent that there are limitations to the effectiveness of these therapies. Nitric oxide (NO) plays an important role in platelet physiology. The ability of NO to regulate cyclic guanosine-3,'5'-monophosphate (cGMP), via activation of soluble guanylate cyclase, is the principal mechanism of negative control over platelet activity. NO is not only of the endothelial source, it is also released from activated platelets, providing a negative feedback. Studies in patients with symptomatic ischemia, chronic heart failure, diabetes and various risk factors for cardiovascular disease have demonstrated that platelets from these subjects exhibit reduced responsiveness to the anti-aggregating efficacy of NO: a phenomenon termed "platelet NO resistance". It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor or EDRF), and as such may contribute to the increased risk of ischemic events. NO resistance also accounts for reduced pharmaco-activity of exogenous NO donors, e.g. organic nitrates. Platelet NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical and inactivation of soluble guanylate cyclase. NO resistance has both diagnostic and prognostic implications. The current review examines the association of platelet NO resistance with pathological hyperaggregability and discusses potential therapeutic strategies targeting this abnormality.

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Section: Glycemic Controlmentioning

confidence: 99%

Platelet Hyperaggregability: Impaired Responsiveness to Nitric Oxide (“Platelet NO Resistance”) as a Therapeutic Target

Rajendran

Chirkov

2008

Cardiovasc Drugs Ther

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“…In those in vitro studies, it was shown that hepatic biotransformation is not required for platelet inhibition by clopidogrel. According to the findings of the study of De La Cruz et al [24], clopidogrel in vitro reduced ADP-induced platelet aggregation and increased endothelial NO production depending on dose. Arrebola et al [25] showed that thromboxane B 2 production and collagen-induced platelet aggregation were inhibited, but prostacyclin synthesis did not change following in vitro incubation with clopidogrel.…”

Section: Discussionmentioning

confidence: 99%

“…Clopidogrel is a drug that has been used for the secondary prevention of atherothrombotic events related to ischemia [46]. Although there are many in vivo reports related to the effects of clopidogrel on platelet functions, there are also various reports about its in vitro effects on platelets [24][25][26]. In those in vitro studies, it was shown that hepatic biotransformation is not required for platelet inhibition by clopidogrel.…”

Section: Discussionmentioning

confidence: 99%

“…In the reactions, 10 μM clopidogrel was used at a final concentration, which is close to the therapeutic concentration in human plasma reported by Cruz et al [24].…”

Section: Drugmentioning

confidence: 99%

“…Several studies have reported that the essential action of thienopyridine derivatives occurs upon their derivatization in the liver [21][22][23]. However, various other studies have reported that clopidogrel had different in vitro antiplatelet effects on platelets [24][25][26]. Although those studies have been carried out in different mediums such as whole blood, isolated platelets or platelet-rich plasma (PRP), the consensus of those studies is that hepatic biotransformation is not required for platelet inhibition by clopidogrel, which seems contrary to most of the in vivo studies.…”

Section: Introductionmentioning

confidence: 99%

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New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

Özsavcı¹,

Şener²,

Oba³

et al. 2010

Turk J Hematol

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Objective: We aimed to detect novel in vitro effects of clopidogrel on platelets by assessment of the following parameters: malondialdehyde, glutathione, nitrite, aggregation response, and expressions of P-selectin, fibrinogen, apolipoprotein A1, apolipoprotein B, and phosphatidylserine. Materials and Methods: Platelets were obtained from healthy (n: 9) and hyperlipidemic (n: 9) volunteers. Expressions of P-selectin, fibrinogen, apolipoproteins A1/B and phosphatidylserine with and without clopidogrel were assayed by flow cytometry. Malondialdehyde, glutathione, aggregation and nitrite levels were also assayed. Results: Without clopidogrel, the baseline values of platelet aggregation, malondialdehyde, and expressions of P-selectin, fibrinogen and phosphatidylserine were significantly higher, whereas nitrite and expression of apolipoproteins A1/B were significantly lower in hyperlipidemics than in the healthy group. In both groups, clopidogrel significantly reduced aggregation and expression of fibrinogen, but it elevated nitrite levels. Clopidogrel significantly decreased P-selectin and phosphatidylserine expression and malondialdehyde but increased expressions of apolipoproteins A1/B only in hyperlipidemics. Conclusion: It seems that clopidogrel has some new in vitro antiplatelet effects. The present study is a basic in vitro study to suggest new insights into the effects of clopidogrel on platelet functions. Özet Amaç: Klopidogrelin trombositler üzerinde yeni in vitro etkilerini tayin etmek: Malondialdehit, glutatyon, nitrit, aggregasyon cevabı, P-selektin, fibrinojen, apolipoprotein A1, apolipoprotein B ve fosfatidilserin ekspresyonları. Yöntem ve Gereçler: Sağlıklı (n: 9) ve hiperlipidemik (n: 9) olgulardan trombositler elde edildi. Klopidogrelli ve klopidogrelsiz trombositlerde P-selektin, fibrinojen, apolipoprotein A1, apolipoprotein B ve fosfatidilserin ekspresyonları flow sitometre ile tayin edildi. Malondialdehit, glutatyon, aggregasyon ve nitrit seviyeleri de tayin edildi. Bulgular: Klopidogrel yokluğunda, hiperlipidemililerde kontrollere göre trombosit agregasyonu, malondialdehit, P-Selektin, fibrinojen ve fosfatidilserin ekspresyonunun başlangıç değerleri yüksek; bununla birlikte nitrit, apolipoprotein A1 ve apolipoprotein B ekspresyonlarınınki ise daha düşüktü. Her iki grupta, klopidogrel anlamlı düzeyde aggregasyonu ve fibrinojen ekspresyonunu azalttı, fakat nitrit seviyelerini artırdı. Klopidogrel sadece hiperlipidemililerde P-selektin ve fosfatidilserin ekspresyonunu ve malondialdehiti azalttı ancak apolipoprotein A1 ve apolipoprotein B ekspresyonlarını artırdı.

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Glycemic Control in Coronary Revascularization

Ujueta

Weiss

Sedlis

et al. 2016

Curr Treat Options Cardio Med

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Hyperglycemia in the setting of coronary revascularization is associated with increased adverse cardiovascular events in patients with or without diabetes mellitus. Data suggest that acute peri-procedural hyperglycemia causes an increase in inflammation, platelet activity, and endothelial dysfunction and is associated with plaque instability and infarct size. While peri-procedural blood glucose level is an independent predictor of adverse outcomes in patients undergoing coronary revascularization, treatment strategies remain uncertain. Randomized clinical trials of glucose-insulin-potassium infusions have consistently shown no benefit, while those comparing insulin therapy versus standard of care have demonstrated mixed results, likely due to the failure to reach euglycemia with these strategies. Although no glucose-lowering agent has been shown to be superior in peri-procedural glycemic control, the continuation of clinically prescribed long-acting glucose-lowering medications in patients with diabetes mellitus prior to coronary angiography and possible percutaneous coronary intervention may be the simplest and most effective approach to maintain euglycemia and decrease the associated increase in inflammation and platelet activity. However, alternative strategies such as therapies targeted at the underlying mechanism of harm (e.g., more potent anti-platelet therapy, anti-inflammatory therapy) should also be considered and warrant further investigation.

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Influence of glucose concentration on the effects of aspirin, ticlopidine and clopidogrel on platelet function and platelet–subendothelium interaction

Cited by 21 publications

References 37 publications

Platelet Hyperaggregability: Impaired Responsiveness to Nitric Oxide (“Platelet NO Resistance”) as a Therapeutic Target

Platelet Hyperaggregability: Impaired Responsiveness to Nitric Oxide (“Platelet NO Resistance”) as a Therapeutic Target

New in vitro effects of clopidogrel on platelets in hyperlipidemic and healthy subjects

Glycemic Control in Coronary Revascularization

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