Aspirin, but not NO-releasing aspirin (NCX-4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation

2004 ◽  
Vol 286 (1) ◽  
pp. G76-G81 ◽  
Author(s):  
John L. Wallace ◽  
Stella R. Zamuner ◽  
Webb McKnight ◽  
Michael Dicay ◽  
Andrea Mencarelli ◽  
...  
Keyword(s):  
Repeated Administration ◽  
Mucosal Injury ◽  
Gastric Damage ◽  
Attractive Alternative ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Cox 2 ◽  
Nitric Oxide Releasing ◽  
Cox 2 Inhibitors ◽  
Ncx 4016

Aceylation of cyclooxygenase (COX)-2 by aspirin can trigger the formation of 15(R)-epilipoxin A4, or aspirin-triggered lipoxin (ATL). ATL exerts protective effects in the stomach. Selective COX-2 inhibitors block ATL synthesis and exacerbate aspirin-induced gastric damage. Nitric oxide-releasing aspirins, including NCX-4016, have antiplatelet effects similar to aspirin but do not cause gastric damage. In the present study, we examined whether or not NCX-4016 triggers ATL synthesis and/or upregulates gastric COX-2 expression and the effects of coadministration of NCX-4016 with a selective COX-2 inhibitor on gastric mucosal injury and inflammation. Rats were given aspirin or NCX-4016 orally and either vehicle or a selective COX-2 inhibitor (celecoxib) intraperitoneally. Gastric damage was blindly scored, and granulocyte infiltration into gastric tissue was monitored through measurement of myeloperoxidase activity. Gastric PG and ATL synthesis was measured as was COX-2 expression. Whereas celecoxib inhibited gastric ATL synthesis and increased the severity of aspirin-induced gastric damage and inflammation, coadministration of celecoxib and NCX-4016 did not result in damage or inflammation. NCX-4016 did not upregulate gastric COX-2 expression nor did it trigger ATL synthesis (in contrast to aspirin). Daily administration of aspirin for 5 days resulted in significantly less gastric damage than that seen with a single dose, as well as augmented ATL synthesis. Celecoxib reversed this effect. In contrast, repeated administration of NCX-4016 failed to cause gastric damage, whether given alone or with celecoxib. These studies support the notion that NCX-4016 may be an attractive alternative to aspirin for indications such as cardioprotection, including in individuals also taking selective COX-2 inhibitors.

Gastritis increases resistance to aspirin-induced mucosal injury via COX-2-mediated lipoxin synthesis

2003 ◽  
Vol 285 (1) ◽  
pp. G54-G61 ◽  
Author(s):  
Marcellus H. L. P. Souza ◽  
Octavio Menezes de Lima ◽  
Stella R. Zamuner ◽  
Stefano Fiorucci ◽  
John L. Wallace
Keyword(s):  
Drinking Water ◽  
Intravital Microscopy ◽  
Mucosal Injury ◽  
The Other ◽  
Gastric Damage ◽  
Protective Effects ◽  
Leukocyte Adherence ◽  
Mucosal Defense ◽  
Cox 2 ◽  
Normal Stomach

Products of cyclooxygenase (COX)-2 contribute to mucosal defense. Acetylation of COX-2 by aspirin has been shown to result in the generation of 15(R)-epi-lipoxin A4, which exerts protective effects in the stomach. In gastritis, it is possible that lipoxin A4 makes a greater contribution to mucosal defense. We tested this hypothesis in the rat, by using the iodoacetamide-induced gastritis model. Iodoacetamide was added to the drinking water for 5 days. Rats were then given aspirin, and the extent of gastric damage was blindly assessed 3 h later. Gastric 15(R)-epi-lipoxin A4 and PGE2 levels were determined. The effects of pretreatment with a selective COX-2 inhibitor, rofecoxib, and of a lipoxin receptor antagonist were assessed. Effects of aspirin and the other test drugs on leukocyte adherence within mesenteric venules were assessed by intravital microscopy. Aspirin elicited greater lipoxin synthesis in the inflamed than in the normal stomach, and there was reduced gastric damage. Rofecoxib inhibited lipoxin synthesis and exacerbated aspirin-induced damage. The lipoxin antagonist also exacerbated aspirin-induced damage. In rats with gastritis, aspirin reduced leukocyte adherence (in contrast to an increase in normal rats), and this effect was reversed by rofecoxib or by the lipoxin antagonist. These results support the notion that aspirin-triggered lipoxin synthesis via COX-2 makes an important contribution to mucosal defense in both the normal and inflamed stomach.

Aspirin, but not no-releasing aspirin (NCX-4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation

2003 ◽  
Vol 124 (4) ◽  
pp. A92
Author(s):  
John L. Wallace ◽  
Andrea Mencarelli ◽  
Piero Del Soldato ◽  
Stefano Fiorucci
Keyword(s):  
Gastric Damage ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Ncx 4016

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

1997 ◽  
Vol 273 (6) ◽  
pp. G1246-G1251 ◽  
Author(s):  
John L. Wallace ◽  
Webb McKnight ◽  
Tammy L. Wilson ◽  
Piero Del Soldato ◽  
Giuseppe Cirino
Keyword(s):  
Nitric Oxide ◽  
Hemorrhagic Shock ◽  
Gastric Damage ◽  
Leukocyte Adherence ◽  
Inhibitory Effects ◽  
Neutrophil Adherence ◽  
Nitric Oxide Releasing ◽  
Derivatives Of ◽  
Ncx 4016

The gastric damage associated with hemorrhagic shock appears to occur, at least in part, through neutrophil-dependent mechanisms. Nitric oxide (NO)-releasing derivatives of aspirin have been shown to spare the gastrointestinal tract of injury. As NO can inhibit neutrophil adherence, it is possible that such a derivative of aspirin (NCX-4016) would exert inhibitory effects on neutrophil adherence and therefore be capable of protecting the stomach against shock-induced gastric damage. This hypothesis was tested in this study. Oral administration of NCX-4016 or glyceryl trinitrate or depletion of circulating neutrophils with antineutrophil serum significantly reduced the extent of gastric damage induced by hemorrhagic shock, whereas aspirin had no effect. NCX-4016 and antineutrophil serum pretreatment resulted in significant preservation of gastric blood flow during the shock period. Moreover, NCX-4016, but not aspirin, was capable of inhibiting N-formyl-Met-Leu-Phe-induced leukocyte adherence to postcapillary mesenteric venules. These results suggest that an NO-releasing aspirin derivative reduces the susceptibility of the stomach to shock-induced damage through inhibitory effects on neutrophil adherence to the vascular endothelium.

Both Selective COX-1 and COX-2 Inhibitors Aggravate Gastric Damage Induced in Rats by 2-Deoxy-D-Glucose

Digestion ◽  
2003 ◽  
Vol 68 (2-3) ◽  
pp. 71-79 ◽  
Author(s):  
Koji Takeuchi ◽  
Tohru Miyazawa ◽  
Masahiro Matsumoto ◽  
Yujiro Hayashi
Keyword(s):  
Gastric Damage ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Synthesis of 1,5-Diarylpyrazoles as Potential COX-2 Inhibitors with Nitric Oxide Releasing Ability

2013 ◽  
Vol 10 (7) ◽  
pp. 594-603
Author(s):  
Bolla Rao ◽  
Meyyappan Muthuppalaniappan ◽  
Saketh Dinavahi ◽  
Srikant Viswanadha ◽  
Chandrakant Bagul ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cox 2 ◽  
Nitric Oxide Releasing ◽  
Cox 2 Inhibitors

COX-2 selective inhibitors cause gastric damage in aspirin treated rats Protective effect of nitroaspirin (NCX-4016)

2001 ◽  
Vol 120 (5) ◽  
pp. A595
Author(s):  
Stefano Fiorucci ◽  
Andrea Mencarelli ◽  
Barbara Palazzetti ◽  
Piero Del Soldato ◽  
Eleonora Distrutti ◽  
...  
Keyword(s):  
Protective Effect ◽  
Gastric Damage ◽  
Selective Inhibitors ◽  
Cox 2 ◽  
Ncx 4016

COX-2: A Molecular Target for Colorectal Cancer Prevention

2005 ◽  
Vol 23 (12) ◽  
pp. 2840-2855 ◽  
Author(s):  
Joanne R. Brown ◽  
Raymond N. DuBois
Keyword(s):  
Biosynthetic Pathway ◽  
Experimental Studies ◽  
Protective Effects ◽  
Randomized Controlled Studies ◽  
Key Enzyme ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Colorectal Cancer Prevention ◽  
Cox 2 Inhibitors

Cyclooxygenase (COX), a key enzyme in the prostanoid biosynthetic pathway, has received considerable attention due to its role in human cancers. Observational and randomized controlled studies in many different population cohorts and settings have demonstrated protective effects of nonsteroidal anti-inflammatory drugs (NSAIDs; the inhibitors of COX activity) for colorectal cancers (CRCs). COX-2, the inducible isoform of cyclooxygenase, is overexpressed in early and advanced CRC tissues, which portends a poor prognosis. Experimental studies have thus identified important mechanisms and pathways by which COX-2 plays an important role in carcinogenesis. Selective COX-2 inhibitors have been approved for use as adjunctive therapy for patients with familial polyposis. The role of COX-2 inhibitors is currently being evaluated for use in wider populations.

COX-2 selective inhibitors cause gastric damage in aspirin treated rats Protective effect of nitroaspirin (NCX-4016)

2001 ◽  
Vol 120 (5) ◽  
pp. A595-A595
Author(s):  
S FIORUCCI ◽  
A MENCARELLI ◽  
B PALAZZETTI ◽  
P SOLDATO ◽  
E DISTRUTTI ◽  
...  
Keyword(s):  
Protective Effect ◽  
Gastric Damage ◽  
Selective Inhibitors ◽  
Cox 2 ◽  
Ncx 4016

The prostacyclin receptor induces human vascular smooth muscle cell differentiation via the protein kinase A pathway

2006 ◽  
Vol 290 (4) ◽  
pp. H1337-H1346 ◽  
Author(s):  
Kristina M. Fetalvero ◽  
Maureen Shyu ◽  
Athena P. Nomikos ◽  
Yuh-Fang Chiu ◽  
Robert J. Wagner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Protein Kinase A ◽  
Cardiovascular Events ◽  
Pcr Analysis ◽  
Protective Effects ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Kinase A

Recent studies of cyclooxygenase-2 (COX-2) inhibitors suggest that the balance between thromboxane and prostacyclin is a critical factor in cardiovascular homeostasis. Disruption of prostacyclin signaling by genetic deletion of the receptor or by pharmacological inhibition of COX-2 is associated with increased atherosclerosis and restenosis after injury in animal models and adverse cardiovascular events in clinical trials (Vioxx). Human vascular smooth muscle cells (VSMC) in culture exhibit a dedifferentiated, migratory, proliferative phenotype, similar to what occurs after arterial injury. We report that the prostacyclin analog iloprost induces differentiation of VSMC from this synthetic, proliferative phenotype to a quiescent, contractile phenotype. Iloprost induced expression of smooth muscle (SM)-specific differentiation markers, including SM-myosin heavy chain, calponin, h-caldesmon, and SM α-actin, as determined by Western blotting and RT-PCR analysis. Iloprost activated cAMP/protein kinase A (PKA) signaling in human VSMC, and the cell-permeable cAMP analog 8-bromo-cAMP mimicked the iloprost-induced differentiation. Both myristoylated PKA inhibitor amide-(14–22) (PKI, specific PKA inhibitor), as well as ablation of the catalytic subunits of PKA by small interfering RNA, opposed the upregulation of contractile markers induced by iloprost. These data suggest that iloprost modulates VSMC phenotype via Gs activation of the cAMP/PKA pathway. These studies reveal regulation of VSMC differentiation as a potential mechanism for the cardiovascular protective effects of prostacyclin. This provides important mechanistic insights into the induction of cardiovascular events with the use of selective COX-2 inhibitors.

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