Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin

Momi, Stefania; Emerson, Michael; Paul, William; Leone, Mario; Mezzasoma, Anna Maria; Soldato, Piero Del; Page, Clive; Gresele, Paolo

doi:10.1016/s0014-2999(00)00223-5

Cited by 63 publications

(61 citation statements)

References 29 publications

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“…In this model, vasodilatory agents, such as calcium antagonists or isosorbide mononitrate, but not antiplatelet agents, exert a protective effect by inducing vasodilation of the lung microvasculature. 23 These results are thus consistent with both an antiplatelet and a vasodilatory activity of dl-and l-nebivolol, which concur to prevent collagen plus epinephrine-induced pulmonary embolism lethality. However, the antithrombotic effect of dl-and l-nebivolol was confirmed in a photochemical injury-induced arterial thrombosis model, known to be platelet mediated 24 and not influenced by vasodilators.…”

Section: Discussionsupporting

confidence: 81%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

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H ypertension is associated with an increased risk of arterial thrombotic events, such as stroke and myocardial infarction, 1 in which platelets are deeply involved. Previous studies have shown that β-adrenoceptor blockers reduce platelet activation and aggregation, 2 but this does not seem to be a class effect because not all β-blockers share this property. 3 dl-Nebivolol (a racemic mixture of d-and l-nebivolol) is a third-generation β 1 adrenoceptor-selective antagonist that, besides its β-blockade-mediated hypotensive effect, possesses direct vasodilatory properties through a mechanism involving the l-arginine/nitric oxide (NO) pathway. 4,5 Of the 2 enantiomers forming the racemic mixture of dl-nebivolol, d-nebivolol, which has an ≈200-fold greater affinity for β 1 -adrenoceptors than that of l-nebivolol, seems to be mainly responsible of selective β-blockade, 6 whereas the l-form is the main effector of the endothelium-dependent vasorelaxant effect. 7,8 dl-Nebivolol exerts its vasodilatory action by activating endothelial nitric oxide synthase (eNOS) and by preventing eNOS uncoupling, thus enhancing NO production. 9 Endothelium-derived NO is a powerful inhibitor of platelet activation and an antithrombotic agent. 10,11 Besides endothelium, eNOS is present in other cells, including platelets, [12][13][14] and several in vitro and in vivo observations in animals and in humans suggest that platelet-derived NO plays a significant anti-inflammatory and antithrombotic role. [15][16][17][18][19] dl-Nebivolol was previously reported to inhibit ADP-and collagen-induced aggregation of human platelets in vitro, 20 an effect prevented by the previous exposure of platelets to a NOS inhibitor, such as L-NG-nitroarginine methyl ester, and enhanced by preincubation with l-arginine, the substrate of NOS, suggesting that the antiplatelet effect of dl-nebivolol is mediated by an enhanced release of NO from platelets. 4 © 2014 American Heart Association, Inc. Objective-dl-Nebivolol, a selective β1-adrenergic receptor antagonist, besides its hypotensive activity exerts vasodilatory and platelet inhibitory effects in vitro by a mechanism involving nitric oxide (NO). Our aim was to evaluate whether nebivolol exerts in vivo antithrombotic effects, to unravel the mechanism of this action and to clarify the relative roles of its 2 enantiomers: d-and l-nebivolol. Methods and Results-In wild-type mice, dl-nebivolol, l-nebivolol, and d-nebivolol, but not bisoprolol, reduced mortality consequent to platelet pulmonary thromboembolism induced by the intravenous injection of collagen plus epinephrine (−44%, −45%, −29%, respectively; P<0.05), whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were effective. dl-Nebivolol, l-and d-nebivolol reduced photochemical damage-induced femoral artery thrombosis in wild-type mice, whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were active. Moreover, dl-nebivolol and l-nebivolol increased plasma, urinary-, and platelet-derived nitrites and nitrates (NOx), NO degradation products, in ...

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Section: Discussionsupporting

confidence: 81%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

Self Cite

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“…In our experimental conditions the eects of NCX4016 are dosedependent and occur at concentrations comparable to those measured in plasma after the oral administration of NCX4016 in experimental animals (Momi et al, 2000;Tagliaro et al, 1997;Wallace et al, 1999). Therefore, the observed inhibition in thromboxane, tissue factor and cytokines in human monocytes support the hypothesis that NCX4016 may have in vivo anti-thrombotic and, possibly, anti-atherosclerotic properties by inhibiting COX activity and releasing NO.…”

Section: Discussionsupporting

confidence: 78%

“…These eects were entirely dependent on the release of NO, since not being achievable through the inhibition of platelet COX (Lechi et al, 1996). When tested in vivo NCX4016 proved to have anti-thrombotic activity even better than ASA, as observed in experimental animals (Momi et al, 2000;Wallace et al, 1999). In addition to these anti-platelet activities, NCX4016 has been recently shown to have cardioprotective eects and to reduce infarct size in experimental miocardial ischaemia and reperfusion.…”

Section: Introductionmentioning

confidence: 99%

NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

Minuz

Degan

Gaino

et al. 2001

British J Pharmacology

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NCX4016 (2 acetoxy‐benzoate 2‐(2‐nitroxymethyl)‐phenyl ester, NicOx S.A., France) is an anti‐thrombotic agent, chemically related to acetylsalicylic acid (ASA) and able to release NO. We tested the effects of NCX4016 and ASA on the release of the thromboxane (TX) A2 metabolite TXB2, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), expression and activity of tissue factor (TF) in stimulated, adherent human monocytes. Both ASA and NCX4016 1 – 1000 μmol l−1 dose‐dependently reduced TXB2 concentration, measured by RIA in the supernatant of 10 μg ml−1 LPS‐stimulated cells. NCX4016 activity was comparable to that of equimolar ASA when incubation lasted 6 h (NCX4016 30 μmol l−1: −86.0±10.1%, NCX4016 300 μmol l−1: −92.2±9.0%, ASA 30 μmol l−1: −92.3±7.5%, ASA 300 μmol l−1: −97.3±1.0%, n=6, M±s.d.). Most of the activity of NCX4016 up to 100 μmol l−1 was prevented by 10 μmol l−1 ODQ, inhibitor of cyclic GMP. NCX4016 100 – 300 μmol l−1 reduced TNF‐α (NCX4016 300 μmol l−1=−77.2±19.9%, n=6) and IL‐6 (NCX4016 300 μmol l−1: −61.9±15.2%, n=6) in LPS stimulated monocytes while ASA had no significant effects. TF activity (NCX4016 300 μmol l−1: 53.7±39.9%, n=4) and immunoreactive TF (NCX4016 300 μmol l−1: −93.9±7.9%, n=7), measured in the supernatant of stimulated cells, were also dose‐dependently inhibited by NCX4016 but not by ASA. The present results indicate that NCX4016 inhibits TXA2 generation as well as cytokine release and TF in human monocytes partly via NO‐dependent mechanisms. NCX4016 may have a favourable profile of activities in the clinical setting of athero‐thrombosis. British Journal of Pharmacology (2001) 134, 905–911; doi:10.1038/sj.bjp.0704326

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“…NO-releasing aspirin has been shown to inhibit thrombus formation in rats and mice (24,35) and to attenuate formylmethionine-leucine-phenylalanine-stimulated and colitis-induced leukocyte adhesion in mesenteric rat venules (36,37). The failure of NCX-4016 (60 mg/kg) to inhibit COX-1 activity in our study agrees with reports of higher doses (compared with aspirin) of NO-aspirin derivatives (NCX-4016 and NCX-4215) being required to inhibit platelet COX-1 activity (34,35).…”

Section: Discussionmentioning

confidence: 99%

Roles of platelet and endothelial cell COX-1 in hypercholesterolemia-induced microvascular dysfunction

Tailor

Wood²,

Wallace³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Aspirin is a common preventative therapy in patients at risk for cardiovascular diseases, yet little is known about how aspirin protects the vasculature in hypercholesterolemia. The present study determines whether aspirin, nitric oxide-releasing aspirin (NCX-4016), a selective cyclooxygenase (COX)-1 inhibitor (SC560), or genetic deficiency of COX-1 prevents the inflammatory and prothrombogenic phenotype assumed by hypercholesterolemic (HC) venules. Aspirin or NCX-4016 (60 mg/kg) was administered orally for the last week of a 2-wk HC diet. COX-1-deficient (COX-1 Ϫ/Ϫ ) and wild-type (WT) mice were transplanted with WT (WT/COX-1 Ϫ/Ϫ ) or COX-1 Ϫ/Ϫ (COX-1 Ϫ/Ϫ /WT) bone marrow, respectively. HC-induced adhesion of platelets and leukocytes in murine intestinal venules, observed with intravital fluorescence microscopy, was greatly attenuated in aspirin-treated mice. Adhesion of aspirin-treated platelets in HC venules was comparable to untreated platelets, whereas adhesion of SC560-treated platelets was significantly attenuated. HC-induced leukocyte and platelet adhesion in COX-1 Ϫ/Ϫ /WT chimeras was comparable to that in SC560-treated mice, whereas the largest reductions in blood cell adhesion were in WT/COX-1 Ϫ/Ϫ chimeras. NCX-4016 treatment of platelet recipients or donors attenuated leukocyte and platelet adhesion independent of platelet COX-1 inhibition. Platelet-and endothelial cell-associated COX-1 promote microvascular inflammation and thrombogenesis during hypercholesterolemia, yet nitric oxide-releasing aspirin directly inhibits platelets independent of COX-1. aspirin; NCX-4016; platelets; leukocytes; cyclooxygenase ASPIRIN THERAPY IS WIDELY used in patients at risk of developing atherosclerosis and thrombosis. The therapeutic efficacy of aspirin in cardiovascular diseases (CVD) is attributed to its platelet-inhibitory function, which results from irreversible inhibition of cyclooxygenase (COX) activity and thromboxane (Tx) generation (2, 33). Although platelets are a rich source of the constitutive isoform of COX (COX-1), endothelial cells also express COX-1 in addition to the inducible isoform, COX-2. This likely accounts for evidence implicating endothelial cell COX-1 inhibition in the beneficial effects of aspirin (but not COX-2 inhibitors) on the inflammation associated with atherosclerotic lesions in apolipoprotein E-deficient and lowdensity lipoprotein receptor-deficient mice (8,25). While the anti-inflammatory action of aspirin in this setting may also result from platelet inhibition (8), nonsteroidal anti-inflammatory drugs (NSAIDs) and their metabolites (i.e., salicylate) can directly interfere with adhesion of inflammatory cells to vascular endothelium, both in vitro (5, 11) and in vivo (1, 6). Hypercholesterolemia, diabetes, hypertension, and other risk factors for CVD promote inflammatory and thrombogenic responses in lesion-prone arteries. Similar responses are detected in microvasculature before the development of atherosclerotic lesions and may render tissues even more vulnerable to ischemic t...

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Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin

Cited by 63 publications

References 29 publications

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

Roles of platelet and endothelial cell COX-1 in hypercholesterolemia-induced microvascular dysfunction

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