Effects of Aggrenox and aspirin on plasma endothelial nitric oxide synthase and oxidised low-density lipoproteins in patients after ischaemic stroke

Summary

Plasma endothelial nitric oxide synthase (eNOS), and oxidised low-density lipoproteins (oxLDL) are established biomarkers of atherosclerosis. We defined the time course and magnitude of changes of plasma eNOS and oxLDL after Aggrenox or aspirin in post-stroke patients. Baseline pretreatment eNOS levels were significantly diminished (110 ± 66pg /ml vs. 374 ± 88 pg/ml, p=0.0001), while oxLDL was twice higher (58 ± 9 mg/l vs. 23 ± 7 mg/l, p=0.004) in post-stroke survivors when compared to controls. Both Aggrenox and aspirin similarly increased plasma eNOS activity. However, oxLDL levels were static after aspirin, but inhibited late after Aggrenox. In the small randomised study, both aspirin and Aggrenox produced fast and sustained recovery of plasma eNOS levels, while only therapy with Aggrenox was associated with oxLDL inhibition late in the trial.

Keywords

Stroke - aspirin - Aggrenox - nitric oxide - oxidised LDL

• References

• 1 Sacco RL, Diener HC, Yusuf S. et al. PRoFESS Study Group.. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359: 1238-1251.
• 2 Schneck MJ. Understanding the PRoFESS study for secondary stroke prevention. Curr Treat Options Cardiovasc Med 2009; 11: 221-31.
• 3 Serebruany V, Sabaeva E, Booze C. et al. Aggrenox Compliance Task Force.. Distribution of dipyridamole in blood components among post-stroke patients treated with extended release formulation. Thromb Haemost 2009; 102: 538-543.
• 4 Serebruany VL, Atar D. The PLATO trial: Do you believe in magic?. Europ Heart J 2010; 31: 764-767.
• 5 Wallentin L, Becker RC, Budaj A. et al. the PLATO Investigators.. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361: 1045-1057.
• 6 Chatterjee A, Black SM, Catravas JD. Endothelial nitric oxide (NO) and its pathophysiologic regulation. Vascul Pharmacol 2008; 49: 134-140.
• 7 Umar S, van der Laarse A. Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem 2010; 333: 191-201.
• 8 Ishigaki Y, Oka Y, Katagiri H. Circulating oxidized LDL: a biomarker and a pathogenic factor. Curr Opin Lipidol 2009; 20: 363-369.
• 9 Itabe H. Oxidative modification of LDL: its pathological role in atherosclerosis. Clin Rev Allergy Immunol. 2009; 37: 4-11.
• 10 Serebruany VL, Malinin AI, Sane DC. et al. Magnitude and time course of platelet inhibition with Aggrenox and aspirin in patients after ischemic stroke. The AGgrenox versus Aspirin Therapy Evaluation (AGATE) Trial. Europ J Pharm 2004; 499: 315-324.
• 11 Diener HC, Cunha L, Forbes C. et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
• 12 ESPRIT Study Group. Halkes PH, van Gijn J, Kappelle LJ. et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial. Lancet 2006; 367: 1665-1673.
• 13 Fitzgerald GA. Drug therapy: Dipyridamole. N Engl J Med 1987; 316: 1247-1257.
• 14 Gibbs CR, Lip GY. Do we still need dipyridamole?. Br J Clin Pharmacol 1998; 45: 323-328.
• 15 Akinboboye OO, Idris O, Chou RL. et al. Absolute quantitation of coronary steal induced by intravenous dipyridamole. J Am Coll Cardiol 2001; 37: 109-116.
• 16 Eisert WG. Near-field amplification of antithrombotic effects of dipyridamole through vessel wall cells. Nerology 2001; 57: S20-23.
• 17 Selly ML, Czeti AL, McGuiness JA. et al. Dipyridamole inhibits the oxidative modification of low density lipoprotein. Atherosclerosis 1994; 111: 91-97.
• 18 Neri Serneri GG, Masotti G, Poggesi L. et al. Enhanced prostacyclin production by dipyridamole in man. Eur J Clin Pharmacol 1981; 21: 9-15.
• 19 Muller TH. Inhibition of thrombus formation by low-dose acethylsalycilic acid, dipyridamole, and their combination in a model of platelet – vessel wall interaction. Neurology 2001; 57: S8-11.
• 20 Singh JP, Rothfuss KJ, Wiernicki TR. et al. Dipyridamole directly inhibits vascular smooth muscle cell profileration in vitro and in vivo: implications in the treatment of restenosis after angioplasty. J Am Coll Cardiol 1994; 23: 665-671.
• 21 Venkatesh PK, Pattillo CB, Branch B. et al. Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrite/nitric oxide-dependent pathway. Cardiovasc Res 2010; 85: 661-670.
• 22 Kim HH, Liao JK. Translational therapeutics of dipyridamole. Arterioscler Thromb Vasc Biol 2008; 28: s39-42.
• 23 Aktas B, Utz A, Hoenig-Liedl P. et al. Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets: in vitro and in vivo/ex vivo studies. Stroke 2003; 34: 764-769.
• 24 Bult H, Fret HR, Jordaens FH, Herman AG. Dipyridamole potentiates platelet inhibition by nitric oxide. Thromb Haemost 1991; 66: 343-349.
• 25 De La Cruz JP, Blanco E, Sánchez de la Cuesta F. Effect of dipyridamole and aspirin on the platelet-neutrophil interaction via the nitric oxide pathway. Eur J Pharmacol 2000; 397: 35-41.
• 26 Iimura O, Kusano E, Amemiya M. et al. Dipyridamole enhances interleukin-1beta-stimulated nitric oxide production by cultured rat vascular smooth muscle cells. Eur J Pharmacol 1996; 296: 319-326.
• 27 Zhao L, Gray L, Leonardi-Bee J. et al. Effect of aspirin, clopidogrel and dipyrida-mole on soluble markers of vascular function in normal volunteers and patients with prior ischaemic stroke. Platelets 2006; 17: 100-104.
• 28 Yamamoto Y, Yamashita T, Kitagawa F. et al. The effect of the long term aspirin administration on the progress of atherosclerosis in apoE-/- LDLR-/- double knockout mouse. Thromb Res 2010; 125: 246-252.
• 29 Taubert D, Berkels R, Grosser N. et al. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol 2004; 143: 159-165.
• 30 Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N. et al. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J Exp Med 2004; 200: 69-78.
• 31 Madajka M, Korda M, White J. et al. Effect of aspirin on constitutive nitric oxide synthase and the biovailability of NO. Thromb Res 2003; 110: 317-321.
• 32 Gamboa A, Abraham R, Diedrich A. et al. Role of adenosine and nitric oxide on the mechanisms of action of dipyridamole. Stroke 2005; 36: 2170-2175.
• 33 Wykretowicz A, Filipiak A, Szczepanik A. et al. Dipyridamole inhibits hydroxyla-mine augmented nitric oxide (NO) production by activated polymorphonuclear neutrophils through an adenosine-independent mechanism. Physiol Res 2004; 53: 645-652.
• 34 Chakrabarti S, Vitseva O, Iyu D. et al. The effect of dipyridamole on vascular cell-derived reactive oxygen species. J Pharmacol Exp Ther 2005; 315: 494-500.
• 35 Selley ML, Bartlett MR, Czeti AL. et al. The role of (E)-4-hydroxy-2-nonenal in platelet activation by low density lipoprotein and iron. Atherosclerosis 1998; 140: 105-112.
• 36 Uno M, Kitazato KT, Nishi K. et al. Raised plasma oxidised LDL in acute cerebral infarction. J Neurol Neurosurg Psychiatry 2003; 74: 312-316.
• 37 Vibo R, Kõrv J, Roose M. et al. Acute phase proteins and oxidised low-density lipoprotein in association with ischemic stroke subtype, severity and outcome. Free Radic Res 2007; 41: 282-287.
• 38 Uno M, Harada M, Takimoto O. et al. Elevation of plasma oxidized LDL in acute stroke patients is associated with ischemic lesions depicted by DWI and predictive of infarct enlargement. Neurol Res 2005; 27: 94-102.
• 39 Uno M, Kitazato KT, Suzue A. et al. Inhibition of brain damage by edaravone, a free radical scavenger, can be monitored by plasma biomarkers that detect oxidative and astrocyte damage in patients with acute cerebral infarction. Free Radic Biol Med 2005; 39: 1109-1116.
• 40 Kurban S, Mehmetoglu I. Effects of acetylsalicylic acid on serum paraoxonase activity, Ox-LDL, coenzyme Q10 and other oxidative stress markers in healthy volunteers. Clin Biochem 2010; 43: 287-290.
• 41 Zhao J, Qi R, Li R. et al. Protective effects of aspirin against oxidized LDL-induced inflammatory protein expression in human endothelial cells. J Cardiovasc Pharmacol 2008; 51: 32-37.
• 42 Mehta JL, Chen J, Yu F. et al. Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res 2004; 64: 243-249.
• 43 Hashimoto A, Miyakoda G, Hirose Y. et al. Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis 2006; 189: 350-357.
• 44 Suzuki K, Uchida K, Nakanishi N. et al. Cilostazol activates AMP-activated protein kinase and restores endothelial function in diabetes. Am J Hypertens 2008; 21: 451-457.
• 45 Park SY, Lee JH, Kim YK. et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation. J Pharmacol Exp Ther 2005; 312: 1241-1248.