Dietary l-Arginine Supplementation Normalizes Platelet Aggregation in Hypercholesterolemic Humans

Wolf, Andreas; Zalpour, Christoff; Theilmeier, Gregor; Wang, Bing Yin; Ma, Adrian; Anderson, Barbara E.; Tsao, Philip S.; Cooke, John P.

doi:10.1016/s0735-1097(97)00523-8

Cited by 157 publications

(103 citation statements)

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“…[3][4][5] Both oral and local administration of the NO precursor L-arginine have been shown to restore vascular NO activity in animals and in humans, 10,17 and this is associated with reduced endothelial adhesiveness for monocytes and inhibition of intimal monocyte accumulation in the vessel wall. 7,11 By contrast, longterm administration of NO synthase antagonists augments endothelial adhesiveness for monocytes and accelerates atherogenesis.…”

Section: No Inhibits Monocyte Bindingmentioning

confidence: 99%

“…Endothelium-derived NO has been shown to antagonize key processes involved in atherogenesis and restenosis. NO inhibits monocyte adherence and chemotaxis, 3 platelet adherence and aggregation, 4,5 and vascular smooth muscle proliferation. 6 Enhancement of NO activity in hypercholesterolemic rabbits reduces monocyte adherence and accumulation, whereas inhibition of NO activity enhances endothelial adhesiveness for monocytes and increases the extent of lesion formation.…”

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confidence: 99%

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Local l -Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis

et al. 1999

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Background-Local administration of L-arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of L-arginine inhibits lesion formation. Methods and Results-New Zealand White rabbits (nϭ56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either L-arginine (800 mg/5 mL with and without 100 Ci L-[2,3-3 H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled L-arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676Ϯ223 versus 453Ϯ93 cpm/mg; PϽ0.02); this was associated with significantly higher NO levels in the L-arginine-treated segments (394.4Ϯ141.6 versus 86.3Ϯ34.3 nmol/mg; PϽ0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with L-arginine as compared with saline infusion (PϽ0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of L-arginine as compared with the saline-treated segments (PϽ0.05). Conclusions-Intramural delivery of L-arginine immediately after angioplasty causes a sustained increase in tissue L-arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.

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Section: No Inhibits Monocyte Bindingmentioning

confidence: 99%

mentioning

confidence: 99%

Local l -Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis

et al. 1999

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“…Our study was not designed to determine whether baseline platelet aggregation was increased in patients with atherosclerosis compared with those without, although previous studies [67][68][69][70][71][72][73][74][75][76][77] have demonstrated increased baseline ex vivo platelet aggregation in patients with atherosclerosis and those with hypercholesterolemia. Our observations that stimulation of endothelial NO activity produces less inhibition of platelet aggregation in patients with atherosclerosis, coupled with previous observations of increased platelet aggregation in this group, suggest that decreased NO activity during stress, a powerful stimulus for endothelial NO production, may contribute to this observed difference in patients with atherosclerosis.…”

Section: Study Limitationsmentioning

confidence: 99%

Effect of Atherosclerosis on Endothelium-Dependent Inhibition of Platelet Activation in Humans

et al. 1998

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Background-We investigated whether luminal release of nitric oxide (NO) contributes to inhibition of platelet activation and whether these effects are reduced in patients with atherosclerosis. Methods and Results-Femoral blood flow velocity and ex vivo whole blood platelet aggregation by impedance aggregometry were measured in femoral venous blood during femoral arterial infusion of acetylcholine (ACh; 30 g/min) in 30 patients, 19 of whom had angiographic atherosclerosis. Measurements were repeated with sodium nitroprusside (40 g/min), L-arginine (160 mol/min), and N G -monomethyl-L-arginine (L-NMMA; 16 mol/min). There was significant inhibition of collagen-induced platelet aggregation with ACh (45Ϯ9.5% lower, PϽ0.001), and this inhibition was greater in patients without atherosclerosis (68.7Ϯ10.4% reduction) than in those with atherosclerosis (32.5Ϯ8.1%, Pϭ0.04). The magnitude of inhibition correlated with vasodilation with ACh, indicating an association between the smooth muscle and antiplatelet effects of endothelium-dependent stimulation. Neither L-NMMA nor sodium nitroprusside altered platelet aggregation. L-Arginine inhibited platelet aggregation equally in vitro (34Ϯ8% reduction, PϽ0.01) and in vivo (37Ϯ13% reduction, PϽ0.01). Conclusions-Stimulation of NO release into the vascular lumen with ACh inhibits platelet aggregation, an effect that is attenuated in patients with atherosclerosis and endothelial dysfunction. Basal NO release does not appear to contribute to platelet passivation in vivo. L-Arginine inhibited platelet aggregation by its direct action on platelets. These findings provide a pathophysiological basis for the observed increase in thrombotic events in atherosclerosis. Use of L-arginine and other strategies to improve endothelial NO activity may impact favorably on thrombotic events in atherosclerosis.(Circulation. 1998;98:17-24.)

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“…All three have been associated with beneficial effects, including improvements in vascular function, systemic inflammatory profile, local inflammation at lesional sites, and an improved platelet profile (4)(5)(6). However, several clinical investigations, particularly long-term studies, have failed to translate these observations into clinical benefit (e.g., refs.…”

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confidence: 99%

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Khambata

Ghosh

Rathod

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO 3 − ) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitratefed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.

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Dietary l-Arginine Supplementation Normalizes Platelet Aggregation in Hypercholesterolemic Humans

Cited by 157 publications

References 50 publications

Local l -Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis

Local l -Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis

Effect of Atherosclerosis on Endothelium-Dependent Inhibition of Platelet Activation in Humans

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

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