Thromb Haemost 2004; 91(05): 1035-1043
DOI: 10.1160/TH03-12-0786
Cell Signaling and Vessel Remodeling
Schattauer GmbH

A novel anti-ischemic nitric oxide donor inhibits thrombosis without modifying haemodynamic parameters

Gemma Vilahur
1   Cardiovascular Research Center, CSIC/ICCC, Hospital of Santa Creu i Sant Pau-UAB, Barcelona, Spain
,
Estefania Segalés
1   Cardiovascular Research Center, CSIC/ICCC, Hospital of Santa Creu i Sant Pau-UAB, Barcelona, Spain
,
Laura Casaní
1   Cardiovascular Research Center, CSIC/ICCC, Hospital of Santa Creu i Sant Pau-UAB, Barcelona, Spain
,
Lina Badimon
1   Cardiovascular Research Center, CSIC/ICCC, Hospital of Santa Creu i Sant Pau-UAB, Barcelona, Spain
› Author Affiliations
Financial support: This study was supported by funds provided by Lacer S.A. and PNS SAF-2000/0174.
Further Information

Publication History

Received 23 December 2003

Accepted after revision 15 February 2004

Publication Date:
01 December 2017 (online)

Summary

Platelets are involved in the clinical presentations of ischemic heart disease. Our objective was to study the antithrombotic effects of a new nitric oxide donor (LA419), a neutral sugar organic nitrate with a protected thiol group in its molecular structure. Animals were randomly distributed in three groups: I) oral administration of LA419 (0.9-1.8-3.6-5 mg/kg/d, 10 days); II) oral administration of standard IS-5-MN (0.9-1.8 mg/kg/d, 10 days); III) non-treated group (control). In catheterized pigs, thrombosis was studied under controlled rheological condi- tions by radioisotopic evaluation of deposited platelets on damaged vessel wall, placed in an extracorporeal perfusion chamber. Changes in blood pressure, heart rate, and platelet aggregation were evaluated. Results have shown that LA419 significantly decreased thrombus formation according to the degree of vascular damage, and shear rate conditions in a dose- dependent manner (p<0.005), without significant modifications on blood pressure and/or elevation of liver enzymes. In contrast, IS-5-MN only showed a significant reduction on plate- let deposition at the high dose, that was associated to hypoten- sion and elevation of liver enzymes. Therefore, we conclude that this new anti-ischemic NO-donor (NOd) LA419 that inhibits platelet function without modifying blood pressure may be a highly efficacious strategy to passivate platelet activation induced by a damaged vessel wall.

 
  • References

  • 1 Thadani U. Treatment of stable angina. Curr Opin Cardiol 1999; 14: 349-58.
  • 2 Fihn SD, Williams SV, Daley J. et al. American College of Cardiology.; American Heart Association.; American College of Physicians-American Society of Internal Medicine. Guidelines for the management of patients with chronic stable angina: treatment. Ann Intern Med 2001; 135: 616-32.
  • 3 Luscher TF, Noll G. The pathogenesis of car-diovascular disease: role of the endothelium as a target and mediator. Atherosclerosis 1995; 118: S81-90.
  • 4 Skvaril J. Nitrates in cardiology practice. Cas Lek Cesk 2000; 139: 343-9.
  • 5 Chirkov YY, Holmes AS, Chirkova LP. et al. Nitrate resistance in platelets from patients with stable angina pectoris. Circulation 1999; 100: 129-34.
  • 6 Wykretowicz A, Dziarmaga M, Szczepanik A. et al. Prospective evaluation of hydroperoxide plasma levels and stable nitric oxide end prod- ucts in patients subjected to angioplasty for coronary artery disease. Int J Cardiol 2003; 89: 173-8.
  • 7 Garcia MMoll. Principles and rules of the use of nitrates. Ann Cardiol Angeiol 1997; 46: 399-405.
  • 8 Chirkov YY, Naujalis JI, Sage RE. et al. Antiplatelet effects of nitroglycerin in healthy subjects and in patients with stable angina pectoris. J Cardiovasc Pharmacol 1993; 21: 384-9.
  • 9 Leopold JA, Loscalzo J. New developments in nitrosovasodilator therapy. Vasc Med 1997; 02: 190-202.
  • 10 International patent number WO 00/20420. Intellectual property world organization. Derivatives of isosorbid mononitrate as vaso- dilator agents with reduced tolerance. .
  • 11 O’Rourke ST, Folts JD, Albretcht RM. Studies on the inhibition of canine platelet aggregation by barbiturates. J Lab Clin Med 1986; 108: 206-12.
  • 12 Meyer B, Badimon JJ, Chesebro JH. et al. Dissolution of mural thrombus by specific thrombin inhibition with r-Hirudin. Compa- rison with heparin and aspirin. Circulation 1998; 97: 681-85.
  • 13 Badimon L, Turitto V, Rosemark JA. et al. Characterization of a tubular flow chamber for studying platelet interaction with biologic and prosthetic materials: deposition of Indium 111-labeled platelets on collagen, subendothe- lium and expanded polytetrafluoroethylene. J Lab Clin Med 1987; 110: 706-18.
  • 14 Goldsmith HK, Turitto VT. Rheological aspects of thrombosis and hemostasis. Thromb Haemost 1986; 55: 415-35.
  • 15 Merrill EW. Rheology of blood. Physiol Rev 1969; 49: 863-88.
  • 16 Jones AL, Bangash IH, Walker J. et al. Portal and systemic haemodynamic response to acute and chronic administration of low and high dose isosorbide-5-mononitrate in patients with cirrhosis. Gut 1995; 36: 104-9.
  • 17 Galvez A, Badimon L, Badimon JJ. et al. Electrical aggregometry in whole blood from humans, pigs and rabbit. Thromb Haemost 1986; 56: 128-36.
  • 18 Royo T, Vidal M, Badimon L. Porcine platelet von Willebrand antigen II (vW AgII): inhibito- ry effect on collagen-induced aggregation and comparative distribution with human platelets. Thromb Haemost 1998; 80: 677-85.
  • 19 Badimon L, Badimon JJ, Galvez A. et al. Influence of arterial damage and wall shear rate on platelet deposition. Arteriosclerosis 1986; 06: 312-20.
  • 20 Sinzinger H, Virgolini I, O’Grady J. et al. Modification of platelet function by isosorbide dinitrate in patients with coronary artery dis- ease. Thromb Res 1992; 65: 323-35.
  • 21 Lam JY, Chesebro JH, Fuster V. Platelets, vasoconstriction, and nitroglycerin during arterial wall injury: a new antithrombotic role for an old drug. Circulation 1988; 78: 712-16.
  • 22 Wallen NH, Larsson PT, Broijersen A. et al. Effects of an oral dose of isosorbide dinitrate on platelet function and fibrinolysis in healthy volunteers. Br J Clin Pharmacol 1993; 35: 143-51.
  • 23 Drummer C, Valta-Seufzer U, Karrenbrock B. et al. Comparison of anti-platelet properties of molsidomine, isosorbide-5-mononitrate and placebo in healthy volunteers. Eur Heart J 1991; 12: 541-49.
  • 24 Fitzgerald DJ, Roy L, Robertson RM. et al. The effects of organic nitrates on prostacyclin biosynthesis and platelet function in humans. Circulation 1984; 70: 297-302.
  • 25 Wallen NH, Andersson A, Hjemdahl P. Effects of treatment with oral isosorbide dinitrate on platelet function in vivo; a double-blind place- bo-controlled study in patients with stable angina pectoris. Br J Clin Pharmacol 1994; 38: 63-70.
  • 26 De Caterina R, Lombardi M, Bernini W. et al. Inhibition of platelet function during in vivo infusion of isosorbide mononitrates: relation- ship between plasma drug concentration and hemodynamic effects. Am Heart J 1990; 119: 855-62.
  • 27 Wang JH, Redmond HP, Wu QD. et al. Nitric oxide mediates hepatocyte injury. Am J Physiol 1998; 275: G1117-26.
  • 28 Kleschyov AL, Oelze M, Daiber A. et al. Does nitric oxide mediate the vasodilator activity of nitroglycerin?. Circ Res 2003; 93: e104-12.
  • 29 Kawabata A. Evidence that endogenous nitric oxide modulates plasma fibrinogen levels in the rat. Br J Pharmacol 1996; 117: 236-7.
  • 30 Ernst E, Resch KL. Fibrinogen as a cardiovas- cular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-63.