Reduction of shock-induced gastric damage by a nitric oxide-releasing aspirin derivative: role of neutrophils

Wallace, John L.; McKnight, Webb; Wilson, Tammy L.; Soldato, Piero Del; Cirino, Giuseppe

doi:10.1152/ajpgi.1997.273.6.g1246

Cited by 59 publications

(80 citation statements)

References 23 publications

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“…However, mice treated orally with equimolar NCX-4016 demonstrated no evidence of gastric injury, which is consistent with previous reports using NO-releasing aspirin (35,37). Furthermore, unlike aspirin, NCX-4016 treatment did not significantly alter platelet COX-1 activity (Fig.…”

Section: No-releasing Aspirin (Ncx-4016) Attenuates Hc-induced Platelsupporting

confidence: 91%

“…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%

“…NOreleasing aspirin 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-4016) inhibits thrombus formation in vivo through a mechanism that appears to be largely dependent on NO release and partially related to a weak inhibitory effect on COX-1-dependent TxA 2 synthesis (34 -36). This NO-releasing NSAID also markedly suppresses formyl-methionine-leucinephenylalanine-induced leukocyte adhesion in rat mesenteric venules (37), an effect that likely results from NO inhibition of leukocyte-endothelial cell adhesion (16). However, whether NO-releasing aspirin provides additional benefit to plain aspirin in modulating the microvascular responses to CVD risk factors, such as hypercholesterolemia, has not been assessed to date.…”

mentioning

confidence: 99%

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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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Section: No-releasing Aspirin (Ncx-4016) Attenuates Hc-induced Platelsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…The drug was also found to be devoid of typical toxic effects of COX-1 inhibitors (NSAIDs) on gastric mucosa also following repeated oral administration. This through inhibition of neutrophil adherence to vascular endothelium [3]. In addition, recent results indicated that NCX4016 is a powerful agent in improving the post-ischemic ventricular dysfunction in the rabbit heart [4] and in reducing the infarct size in rat heart induced by ischemia-reperfusion [5].…”

Section: Introductionmentioning

confidence: 99%

In vitro metabolism of a nitroderivative of acetylsalicylic acid (NCX4016) by rat liver: LC and LC–MS studies

Carini

Aldini

Orioli

et al. 2002

Journal of Pharmaceutical and Biomedical Analysis

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The metabolism of a nitroderivative of acetylsalicylic acid, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX4016), the lead compound of a new class of NO-releasing non steroidal-antiinflammatory drugs has been studied in vitro in rat liver subcellular fractions (S 9000 × g, microsomes, cytosol). Samples were extracted with CH 3 CN (2 vol.) containing 1% H 3 PO 4 (2 M), vortexed for 3 min and then centrifuged for 5 min at 5000 rpm. Supernatants were diluted with 0.02 M phosphoric acid and analysed by reverse-phase LC. Linearity of calibration for NCX4016 and metabolites was observed over the range 0.25-50 mg/ml with coefficients of determination greater than 0.9996. Extraction efficiency from spiked liver samples ranged from 85 to 95% for all the analytes. In the S 9000×g fraction, NCX4016 undergoes rapid metabolization, with the formation of salicylic acid (SA) and [3-(nitrooxymethyl)phenol] (HBN). HBN is then rapidly metabolised to 3-hydroxybenzylalcohol (HBA), and mainly to a new metabolic species, whose formation takes place specifically in the liver cell cytosol. LC-MS analysis (electrospray ionisation) of the cytosol extract in negative and positive-ion modes furnished deprotonated [M − H] − and protonated [M +H] + molecular ions at m/z 412 and 414, respectively, accompanied by the typical clusters with sodium. MS/MS analysis in negative-ion mode, by selection and collision of the ion at m/z 412, gave a fragmentation pattern characterized by the ions at m/z 272 and 254, which allowed to assign the structure of 1-(glutathion-Syl)methylene-3-hydroxy-benzene, a conjugated product between GSH and the benzyl carbon atom of HBN. In rat liver cytosol HBN is completely metabolised to this thioether adduct within 30 min incubation; the process is enzymatically mediated by GSH transferase and strictly dependent on GSH availability. The relevance of this new metabolic pathway in NCX4016 detoxification by rat liver is discussed.

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“…Part of the protective effect of H 2 S may be related to its ability, like NO [16], to suppress leukocyte adherence to the vascular endothelium [17], a crucial event in the pathogenesis of ischemia-reperfusion injury that contributes to prolonged impairment of tissue perfusion after the ischemic period. The more quickly blood flow can be restored to the mucosa, the less tissue injury will occur.…”

mentioning

confidence: 99%

Hydrogen Sulfide: A Rescue Molecule for Mucosal Defence and Repair

Wallace

2012

Dig Dis Sci

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Reduction of shock-induced gastric damage by a nitric oxide-releasing aspirin derivative: role of neutrophils

Cited by 59 publications

References 23 publications

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

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

In vitro metabolism of a nitroderivative of acetylsalicylic acid (NCX4016) by rat liver: LC and LC–MS studies

Hydrogen Sulfide: A Rescue Molecule for Mucosal Defence and Repair

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