Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication

Paolo Gresele; Rino Migliacci; Alessandra Procacci; Paola De Monte; Erminio Bonizzoni

doi:10.1160/TH06-10-0555

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 97(03): 444-450
DOI: 10.1160/TH06-10-0555

Endothelium and Vascular Development

Schattauer GmbH

Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication

Paolo Gresele

¹Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy

,

Rino Migliacci

¹Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy

,

Alessandra Procacci

¹Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy

,

Paola De Monte

¹Department of Internal Medicine, Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy

,

Erminio Bonizzoni

²Institute of Medical Statistics and Biometry, University of Milan, Milan, Italy

› Institutsangaben

Abstract

Summary

Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day I (pre-treatment: aspirin = 3.1 ± 0.5%, nitroaspirin = 3.9 ± 0.7%, p=NS), and on day 28 (aspirin = 3.4 ± 0.7%, NCX 4016 = 3.2 ± 0.6%, p=NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = –1.15%, nitroaspirin = –1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirin-treated group (- 1.46%) while it was abolished in the NCX 4016-treated group (+ 0.79%, p= 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-l which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.

Keywords

Flow-mediated vasodilation - intermittent claudication - ischemia/reperfusion injury - nitric oxide

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References
1 Lee AJ, Price JF, Russell MJ. et al. Improved prediction of fatal myocardial infarction using the Ankle Brachial Index in addition to conventional risk factors. The Edinburgh Artery Study. Circulation 2004; 110: 3075-3080.
2 Brevetti G, Martone VD, De Cristofaro T. et al. High levels of adhesion molecules are associated with impaired endothelium-dependent vasodilation in patients with peripheral arterial disease. Thromb Haemost 2001; 85: 63-66.
3 Widlansky ME, Gokce N, Keaney Jr JF. et al. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003; 42: 1149-1160.
4 Gokce N, Keaney Jr JF, Hunter LM. et al. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003; 41: 1769-1775.
5 Brevetti G, Silvestro A, Schiano V. et al. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation 2003; 108: 2093-2098.
6 Turton EPL, Coughlin PA, Kester RC. et al. Exercise training reduces the acute inflammatory response associated with claudication. Eur J Vasc Endovasc Surg 2002; 23: 309-316.
7 Kharbanda RK, Peters M, Walton B. et al. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation 2001; 103: 1624-1630.
8 Nawaz S, Walker RD, Wilkinson CH. et al. The inflammatory response to upper and lower limb exercise and the effects of exercise training in patients with claudication. J Vasc Surg 2001; 33: 392-399.
9 Silvestro A, Scopacasa F, Oliva G. et al. Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication. Atherosclerosis 2002; 165: 277-283.
10 Hare JM. Nitroso-redox balance in the cardiovascular system. N Engl J Med 2004; 351: 2112-2114.
11 Wolf A, Zalpour C, Theilmeier G. et al. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol 1997; 29: 479-485.
12 Davi G, Gresele P, Violi F. et al. Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation 1997; 96: 69-75.
13 Hallstrom S, Gasser H, Neumayer C. et al. S-nitroso human serum albumin treatment reduces ischemia/ reperfusion injury in skeletal muscle via nitric oxide release. Circulation 2002; 105: 3032-3038.
14 Gresele P, Momi S, Mezzasoma AM. NCX4016: a novel antithrombotic agent. Dig Liver Dis 2003; 35 (Suppl. 02) (Suppl) S20-S26.
15 Pieper GM, Siebeneich W, Olds CL. et al. Vascular protective actions of a nitric oxide aspirin analog in both in vitro and in vivo models of diabetes mellitus. Free Radic Biol Med 2002; 32: 1143-1156.
16 Momi S, Pitchford SC, Alberti PF. et al. Nitroaspirin plus clopidogrel versus aspirin plus clopidogrel against platelet thromboembolism and intimal thickening in mice. Thromb Haemost 2005; 93: 535-543.
17 Gresele P, Migliacci R. Extrapolation of trial results suggests that aspirin is useful in intermittent claudication. Brit Med J 1998; 317: 1587-1588.
18 Creager MA, Jones DW, Easton JD. et al. Atherosclerotic vascular disease conference: Writing Group V: medical decision making and therapy. Circulation 2004; 109: 2634-2642.
19 Berti F, Rossoni G, Magni F. et al. Nonsteroidal antiinflammatory drugs aggravate acute myocardial ischemia in the perfused rabbit heart: a role for prostacyclin. J Cardiovasc Pharmacol 1988; 12: 438-444.
20 Fiorucci S, Santucci L, Gresele P. et al. Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology 2003; 124: 600-607.
21 Gresele P, Momi S. Pharmacological profile and therapeutic potential of NCX 4016, a nitric-oxide releasing aspirin, for cardiovascular disorders. Cardiovasc Drug Rev 2006; 24: 148-168.
22 Gresele P, Migliacci R, Di Sante G. et al. Effect of cloricromene on intermittent claudication. A randomized, double-blind, placebo-controlled trial in patients treated with aspirin: effect on claudication distance and quality of life. CRAMPS Investigator Group. Cloricromene Randomized Arteriopathy Multicenter Prospective Study. Vasc Med 2000; 5: 83-89.
23 Corretti MC, Anderson TJ, Benjamin EJ. et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. A report of the international brachial artery reactivity task force. J Am Coll Cardiol 2002; 39: 257-265.
24 Pernow J, Böhm F, Beltran E. et al. L-Arginine protects from ischemia-reperfusion-induced endothelial dysfuntion in humans in vivo. J Appl Physiol 2003; 95: 2218-2222.
25 Muzaffar S, Shukla N, Angelini G. et al. Nitroaspirins and morpholinosydnonimine but not aspirin inhibit the formation of superoxide and the expression of gp91phox induced by endotoxin and cytokines in pig pulmonary artery vascular smooth muscle cells and endothelial cells. Circulation 2004; 110: 1140-1147.
26 Emanueli C, Van Linthout S, Salis MB. et al. Nitric oxide-releasing aspirin derivative, NCX 4016, promotes reparative angiogenesis and prevents apoptosis and oxidative stress in a mouse model of peripheral ischemia. Arterioscler Thromb Vasc Biol 2004; 24: 2082-2087.
27 Minuz P, Degan M, Gaino S. et al. NCX4016 (NOAspirin) has multiple inhibitory effects in LPS-stimulated human monocytes. Br J Pharmacol 2001; 134: 905-911.
28 Gori T, Burstein JM, Ahmed S. et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation 2001; 104: 1119-1123.
29 Schulz E, Tsilimingas N, Rinze R. et al. Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation 2002; 105: 1170-1175.
30 Muller S, Laber U, Mullenheim J. et al. Preserved endothelial function after long-term eccentric isosorbide mononitrate despite moderate nitrate tolerance. J Am Coll Cardiol 2003; 41: 1994-2000.
31 Carini M, Aldini G, Orioli M. et al. Chemiluminescence and LC-MS/MS analyses for the study of nitric oxide release and distribution following oral administration of nitroaspirin (NCX 4016) in healthy volunteers. J Pharm Biomed Anal 2004; 35: 277-287.
32 De Berrazueta JR, Sampedro I, Garcia-Unzueta MT. et al. Effect of transdermal nitroglycerin on inflammatory mediators in patients with peripheral atherosclerotic vascular disease. Am Heart J 2003; 146: E14-E20.
33 Wijnen MHWA, Coolen SAJ, Vader HL. et al. Antioxidants reduce oxidative stress in claudicants. J Surg Res 2001; 96: 183-187.
34 Hingorani AD, Cross J, Kharbanda RK. et al. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 2000; 102: 994-999.
35 Ghiadoni L, Donald AE, Cropley M. et al. Mental stress induces transient endothelial dysfunction in humans. Circulation 2000; 102: 2473-2478.
36 Plotnick GD, Corretti MC, Vogel RA. Effect of antioxidant vitamins on the transient impairment of endothelium- dependent brachial artery vasoactivity following a single high-fat meal. J Am Med Assoc 1997; 278: 1682-1686.
37 Heiss C, Kleinbongard P, Dejam A. et al. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol 2005; 46: 1276-1283.
38 Dupuis J, Tardif J-C, Cernacek P. et al. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999; 99: 3227-3233.
39 Kojda G, Hambrecht R. Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy?. Cardiovasc Res 2005; 67: 187-197.
40 Modena MG, Sonetti L, Coppi F. et al. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol 2002; 40: 505-510.