2007 - 10

J Thorac Cardiovasc Surg. 2007 Oct;134(4):1033-9.

Nitric oxide-donating aspirin (NCX 4016) inhibits neointimal thickening in a pig model of saphenous vein-carotid artery interposition grafting: a comparison with aspirin and morpholinosydnonimine (SIN-1).

Wan S, Shukla N, Angelini GD, Yim AP, Johnson JL, Jeremy JY. Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China.

OBJECTIVE: Despite its proven value in reducing thrombotic complications in patients undergoing coronary artery bypass graft surgery, aspirin does not reduce the incidence of late vein graft failure. It was suggested, therefore, that co-administration of nitric oxide with aspirin may compensate for these limitations. A drug class that fulfills this pharmacologic criterion is nitric oxide-donating aspirin (NCX 4016). METHODS: The effect of administration of the aspirin-nitric oxide adduct, NCX 4016, compared with those of aspirin alone and the nitric oxide donor, morpholinosydnonimine, alone (once daily for 1 month) on thickening of saphenous vein-carotid artery interposition grafts was investigated. RESULTS: NCX 4016, at 10 mg, 30 mg, and 60 mg x kg(-1) x d(-1), inhibited neointimal thickness and area in porcine vein grafts. Aspirin alone (60 mg x kg(-1) x d(-1)) and morpholinosydnonimine alone (1 mg x kg(-1) x d(-1)), also inhibited neointimal thickness and neointimal area, although they were less potent than NCX 4016. At 30 mg x kg(-1) x d(-1), aspirin had no effect. Compared with untreated controls, NCX 4016 had little effect on medial thickness or area at 10 mg/kg or 30 mg x kg(-1) x d(-1) but had a significant effect at 60 mg x kg(-1) x d(-1). Aspirin alone and morpholinosydnonimine alone also inhibited medial thickness and area. NCX 4016 at 60 mg x kg(-1) x d(-1) and aspirin at 60 mg x kg(-1) x d(-1) increased luminal area. CONCLUSIONS: The range of properties displayed by NCX 4016 (inhibition of neointima formation, gastroprotection, antithrombotic and antiatherogenic effects) renders them potentially useful in treating both early and late vein graft failure and indicates that a clinical study on this novel drug class in patients undergoing coronary bypass grafting is warranted.

Am J Physiol Heart Circ Physiol. 2007 Oct 12; [Epub ahead of print]

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

Tailor A, Wood KC, Wallace JL, Specian RD, Granger DN. Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana, United States.

Aspirin is 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, NO-releasing aspirin (NCX-4016), a selective 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 wk of a 2 wk HC diet. COX-1 deficient (COX-1(-/-)) and wild type (WT) mice were transplanted with WT (WT/COX(-1-/-)) or COX-1(-/-) (COX-1(-/-)/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, while adhesion of SC560-treated platelets was significantly attenuated. HC-induced leukocyte and platelet adhesion in COX-1(-/-)/WT chimeras were comparable to SC560-treated mice, while the largest reductions in blood cell adhesion were in WT/COX-1(-/-) 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 NO-releasing aspirin directly inhibits platelets independent of COX-1. Key words: Aspirin, NCX-4016, cyclooxygenase, platelets, leukocytes.

Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1545-52. Epub 2007 May 25.

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats.

Fu Y, Wang Z, Chen WL, Moore PK, Zhu YZ. Cardiovascular Biology Research Group, National University of Singapore.

In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg.kg(-1).day(-1)), and NO-aspirin (56 mg.kg(-1).day(-1)). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n = 23), aspirin (n = 22), and NO-aspirin groups (n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 +/- 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 +/- 1.8 and 22.9 +/- 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemia-reperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.

Biochem Soc Trans. 2007 Oct;35(Pt 5):1364-8.

Novel agents for cancer prevention based on nitric oxide.

Rigas B. Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794-5200, U.S.A.

NO (nitric oxide) biology has provided the impetus for the development of anticancer agents based on their ability to release NO. NO-NSAIDs (NO-donating non-steroidal anti-inflammatory drugs), consisting of a conventional NSAID to which an NO-releasing moiety is covalently attached, are promising chemopreventive agents against cancer. Compared with their parent compounds, NO-NSAIDs are up to several hundred times more potent in inhibiting the growth of cancer cell lines and prevent colon and pancreatic cancer in animal models. Their chemopreventive effect is due to inhibition of proliferation, induction of cell death and inhibition of cell-cycle-phase transitions. NO-ASA (NO-aspirin), the best-studied NO-NSAID, induces oxidative stress in target cells. Major downstream signalling effects involve the Wnt, NOS2 (nitric oxide synthase 2), MAPK (mitogen-activated protein kinase), NF-kappaB (nuclear factor kappaB) and Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) pathways. NO-NSAIDs, particularly NO-ASA, appear to be safe compounds, as suggested by many animal and early human studies. An ongoing clinical trial is designed to determine whether NO-ASA can inhibit early stages of colon carcinogenesis in subjects at risk for colon cancer. It is clinical trials that will ultimately determine the role of NO-NSAIDs in cancer prevention and perhaps treatment.