N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

Stamler, Jonathan S.; Mendelsohn, Michael E.; Amarante, Patricia; Smick, D.; Andon, N.; Davies, Peter F.; Cooke, John P.; Loscalzo, Joseph

doi:10.1161/01.res.65.3.789

Cited by 231 publications

(134 citation statements)

References 39 publications

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“…Endothelial dysfunction, including decreased endothelial cell-dependent vasorelaxation, is increasingly proposed to be triggered by free radicals generated during auto-oxidation of homocysteine (Loscalzo, 1996). According to the work of , homocysteine auto-oxidation might prevent thiol nitrosation that, under normal physiologic conditions, sustains the antiplatelet and vasorelaxing activities of NO by increasing the stability of NO (Simon et al, 1993;Stamler et al, 1989). Conversely, this autooxidation, which is detrimental to the nitrosothiol formation, contributes to the production of highly reactive peroxynitrite resulting from the reaction between superoxide anions and NO.…”

Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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“…31,49,50 Nitrosothiols have also been shown to inhibit platelet aggregation. 24,51 Antioxidant flavonoids in tea may also inhibit platelet aggregation by a number of mechanisms. 11 Tea also contains caffeine, and caffeine consumption has been shown in recent studies to inhibit platelet aggregation, possibly by upregulation of adenosine A 2A receptors.…”

Section: Duffy Et Al Tea Effects On Platelet Aggregationmentioning

confidence: 99%

“…14 Flavonoids also enhance nitric oxide (NO) production from the endothelium. 22 NO is a potent inhibitor of platelet adhesion, aggregation, [23][24][25] and thrombosis, 26 and impaired platelet production of NO has been associated with acute coronary syndromes. 27 A recent study demonstrated dose-dependent inhibition of human platelet aggregation in vitro with green tea catechins, which are important tea flavonoids.…”

mentioning

confidence: 99%

Effect of Acute and Chronic Tea Consumption on Platelet Aggregation in Patients With Coronary Artery Disease

Duffy

Vita

Holbrook

et al. 2001

ATVB

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Abstract-Epidemiological studies suggest that tea consumption is associated with a decreased risk of cardiovascular events, but the mechanisms of benefit remain undefined. Platelet aggregation is a precipitating event in cardiovascular disease, and tea contains antioxidant flavonoids that are known to decrease platelet aggregation in vitro. To test the effect of tea consumption on platelet aggregation, we randomized 49 patients with coronary artery disease to either 450 mL of black tea or water consumed initially, followed by 900 mL of tea or water daily for 4 weeks in a crossover design. Ex vivo platelet aggregation in platelet-rich plasma was assessed in response to ADP and thrombin receptor-activating peptide at baseline and 2 hours and 4 weeks after beverage consumption. We observed dose-dependent platelet aggregation in response to each agonist, and neither relation was altered by acute or chronic tea consumption. Plasma flavonoids increased with acute and chronic tea consumption, indicating adequate absorption of tea flavonoids. In conclusion, these results demonstrate that acute and chronic black tea consumption does not affect ex vivo platelet aggregation in patients with coronary artery disease. These findings suggest that an effect of tea flavonoids on platelet aggregation is unlikely to be the explanation for the reduction in risk of cardiovascular events noted in epidemiological studies. Key Words: platelet aggregation Ⅲ tea Ⅲ flavonoids Ⅲ coronary artery disease R ecent epidemiological studies strongly suggest an inverse relationship between tea consumption and cardiovascular disease risk, 1-5 with 1 notable exception. 6 There is also convincing evidence that dietary intake of antioxidant flavonoids from tea and other sources (eg, red wine, onions, apples, and broccoli) is associated with reduced cardiovascular risk. [1][2][3][4][5][7][8][9] The benefit of high flavonoid intake may be greater for individuals with established coronary artery disease (CAD), 1,10 although favorable effects have also been demonstrated in people without evidence of atherosclerosis. 5,8,9 One proposed mechanism for the apparent benefit of tea and other sources of flavonoids is their favorable effect on platelet aggregation. [11][12][13][14][15][16] These polyphenols may inhibit platelet aggregation by a number of different mechanisms, including inhibition of lipoxygenase, cyclooxygenase, 13,17 cAMP phosphodiesterase, 12,18 and cGMP phosphodiesterase. 19 Other platelet-inhibitory effects of flavonoids include thromboxane receptor antagonism, 15 scavenging of reactive oxygen species such as superoxide anion, 20 decreasing phospholipase C activation by blunting hydrogen peroxide production, 21 and inhibition of lipid peroxidation. 14 Flavonoids also enhance nitric oxide (NO) production from the endothelium. 22 NO is a potent inhibitor of platelet adhesion, aggregation, [23][24][25] and thrombosis, 26 and impaired platelet production of NO has been associated with acute coronary syndromes. 27 A recent study demonstrated dose-...

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“…Advantages of NAC treatment could also be attributed to its vaso-relaxant properties [37], most probably via formation of S-nitrosocysteine [38].…”

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

Taut¹,

Schmidt²,

Zapletal

et al. 2001

Clinical and Experimental Immunology

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SUMMARYIn orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P # 0´02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment.

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N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

Cited by 231 publications

References 39 publications

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Effect of Acute and Chronic Tea Consumption on Platelet Aggregation in Patients With Coronary Artery Disease

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

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