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Thromb Haemost 1988; 59(02): 207-211
DOI: 10.1055/s-0038-1642755
Original Articles
Schattauer GmbH Stuttgart

Organic Nitrates: Direct Antiplatelet Effects and Synergism with Prostacyclin

Antiplatelet Effects of Organic Nitrates
Raffaele De Caterina
The CNR Institute of Clinical Physiology and Istituto di Patologia Medica I, University of Pisa, Pisa, Italy
,
Daniela Giannessi
The CNR Institute of Clinical Physiology and Istituto di Patologia Medica I, University of Pisa, Pisa, Italy
,
Walter Bernini
The CNR Institute of Clinical Physiology and Istituto di Patologia Medica I, University of Pisa, Pisa, Italy
,
Annamaria Mazzone
The CNR Institute of Clinical Physiology and Istituto di Patologia Medica I, University of Pisa, Pisa, Italy
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Publikationsverlauf

Received 25. Juni 1987

Accepted after revision 25. November 1987

Publikationsdatum:
21. Mai 2018 (online)

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Summary

Isosorbide dinitrate inhibits platelet function in vivo at concentrations about 10 times lower than in vitro (10-7 -10-6 vs. 10-6 -10-5 M). We investigated two possible reasons for this difference. Isosorbide dinitrate and its in vivo longer-lived metabolites, isosorbide-2- and isosorbide-5-mononitrate were incubated for 5 min with human platelet-rich plasma or washed platelets; irreversible aggregation was induced with threshold doses of ADP, adrenaline, collagen, arachidonic acid and thrombin, and thromboxane (TX) B2 production was measured by radioimmunoassay. Moreover, the concentration of exogenous prostacyclin required to inhibit platelet aggregation by 50% (IC50) after preincubation with isosorbide dinitrate or vehicle was determined. At 10-7 M, only isosorbide-2-mononitrate inhibited aggregation (-12%, p >0.05) and TX production (-36%, p >0.01) by ADP. At 10-6 M isosorbide-2-mononitrate inhibited aggregation by adrenaline more than the dinitrate (-41% vs. -25%, p >0.05). In addition, at supra-threshold doses of all the aggregating agents, isosorbide dinitrate decreased IC50 of prostacyclin from 2.7 ± 1.2 to 0.36 ± 0.2 nM. Generation of a platelet-active metabolite and synergism with prostacyclin are new properties of isosorbide dinitrate that may account for antiplatelet effects in vivo.

Keywords

Nitrates - Isosorbide dinitrate - Platelets - Prostacyclin
 

  • References

  • 1 Schafer AI, Alexander RW, Handin RI. Inhibition of platelet function by organic nitrate vasodilators. Blood 1980; 55: 649-654
    PubMedGoogle Scholar
  • 2 Rossi EC, Lichtental PR, Michaelis LL, Fung HL. Nitroglycerin, prostacyclin and platelet function. In: Prostaglandins in clinical medicine: cardiovascular and thrombotic disorders Wu KK, Rossi EC L. eds. pp 75-79 Year Book Medical Publishers; Chicago: 1981
    Google Scholar
  • 3 De Caterina R, Giannessi D, Crea F, Chierchia S, Bernini W, Gazzetti P, L’Abbate A. Inhibition of platelet function by injectable isosorbide dinitrate. Am J Cardiol 1984; 53: 1683-1687
    CrossrefPubMedGoogle Scholar
  • 4 Fuster V, Steele PM, Chesebro JH. Role of platelets and thrombosis in coronary atherosclerotic disease and sudden death. J Am Coll Cardiol 1985; 5: 175B-184B
    CrossrefPubMedGoogle Scholar
  • 5 Garattini SG. Platelet-drug interactions: an open field. In: Platelets: A Multidisciplinary Approach De Gaetano G, Garattini S. eds Raven Press; New York: 1978. pp 61-73
    Google Scholar
  • 6 De Caterina R, Dorso CR, Tack-Goldman K, Weksler BB. Nitrates and endothelial prostacyclin production: studies in vitro. Circulation 1985; 71: 176-82
    CrossrefPubMedGoogle Scholar
  • 7 De Caterina R, Giannessi D, Bernini W, Gazzetti P, Michelassi G, L’Abbate A, Donato L, Patrignani P, Eur Heart J. 1985; 6: 409-417
    PubMed
  • 8 Aster RH, Jandl JH. Platelet sequestration in man I. Methods J Clin Invest 1964; 43: 843-849
    CrossrefPubMedGoogle Scholar
  • 9 Kinlough-Rathbone RL, Mustard JF, Packham MA, Perry DW, Reimers HJ, Cazenave JP. Properties of washed human platelets. Thromb Haemostas 1977; 37: 291-308
    PubMedGoogle Scholar
  • 10 Cazenave JP, Hemmendinger S, Beretz A, Sutter-Bay A, Launay J. L’agregation plaquetaire: outil d’investigation clinique et d’etude pharmacologique. Methodologie Ann Biol Clin 1983; 41: 167-179
    PubMedGoogle Scholar
  • 11 Giannessi D, De Caterina R, Gazzetti P, Bernini W, Masini S, Zucchelli GC. Methodological assessment and applications of a radioimmunoassay for thromboxane (TX)B2 to measurement of TXB, release by platelets. J Nucl Med All Sci 1982; 26: 25-34
    PubMedGoogle Scholar
  • 12 De Caterina R, Giannessi D, Gazzetti P, Bernini W. Thromboxane B2 generation during ex-vivo platelet aggregation. J Nucl Med All Sci 1984; 28: 185-196
    PubMedGoogle Scholar
  • 13 McGregor M. Pathogenesis of angina pectoris and role of nitrates in relief of myocardial ischemia. Am J Med 1983; 74: 21-27
    CrossrefPubMedGoogle Scholar
  • 14 Feldman RL, Conti R. Relief of myocardial ischemia with nitroglycerin: what is the mechanism?. Circulation 1981; 64: 1098-1100
    CrossrefPubMedGoogle Scholar
  • 15 Kaski JC, Rodriguez Plaza L, Meran O, Araujo L, Chierchia S, Maseri A. Improved coronary supply: prevailing mechanism of action of nitrates in chronic stable angina. Am Heart J 1985; 110: 238-245
    CrossrefPubMedGoogle Scholar
  • 16 Packer M. Mechanism of nitrate action in patients with severe left ventricular failure: conceptual problems with the theory of venosequestration. Am Heart J 1985; 110: 259-264
    CrossrefPubMedGoogle Scholar
  • 17 Parmley WW. Role of isosorbide dinitrate in management of chronic congestive heart failure. Am Heart J 1985; 110: 264-268
    CrossrefPubMedGoogle Scholar
  • 18 Taylor T, Chasseaud LF. Pharmacokinetics of isosorbide dinitrate in human subjects. In: Nitrates III. Cardiovascular effects Lichtlen PR, Engel HJ, Schrey A, Swan HJ C. editors: Springer Verlag; Berlin: 1981. pp 40-46
    Google Scholar
  • 19 Abshagen U. Pharmacokinetics of ISDN, sustained-release ISDN, and IS-5-MN. In: Mononitrates Cohn JN, Rittinghausen R. editors: Springer Verlag, Berlin, Heidelberg; New York, Tokyo: pp 53-66
    Google Scholar
  • 20 Fung HL, McNiff EF, Ruggirello D, Darke AC, Thadani U, Parker JO. Kinetics of isosorbide dinitrate and relationship to pharmacological effects. Br J Clin Pharmacol 1981; 11: 579-590
    CrossrefPubMedGoogle Scholar
  • 21 Armstrong PW, Moffat JA, Marks GS. Arterial-venous nitroglycerin gradient during intravenous infusion in man. Circulation 1982; 66: 1273-1276
    CrossrefPubMedGoogle Scholar
  • 22 Levin RI, Jaffe EA, Weksler BB, Tack-Goldman K. Nitroglycerin stimulates synthesis of prostacyclin by human endothelial cells. J Clin Invest 1981; 67: 762-769
    CrossrefPubMedGoogle Scholar
  • 23 Schroer K, Grodzinska L, Darius H. Stimulation of coronary vascular prostacyclin and inhibition of human platelet thromboxane A2 after low-dose nitroglycerin. Thromb Res 1981; 23: 59-67
    CrossrefPubMedGoogle Scholar
  • 24 Mehta J, Mehta P, Roberts A, Faro R, Ostrowski N, Brigmon L. Comparative effects of nitroglycerin and nitroprusside on prostacyclin generation in adult human vessel wall. J Am Coll Cardiol 1983; 6: 625-630
    PubMedGoogle Scholar
  • 25 Panzenbeck MJ, Baez A, Kaley G. Nitroglycerin and nitroprusside increase coronary blood flow in dogs by a mechanism independent of prostaglandin release. Am J Cardiol 1984; 53: 936-940
    CrossrefPubMedGoogle Scholar
  • 26 Feigen LP, Chapnick BM, Flemming JE, Kadowitz PJ. Prostaglandins: renal vascular responses to bradykinin, histamine and nitroglycerin. Am J Physiol 1978; 234: H 496-597
    PubMedGoogle Scholar
  • 27 Simonetti I, De Caterina R, Michelassi C, Marzilli M, De Nes M, L’Abbate A. Coronary vasodilation by nitrates is not mediated by the prostaglandin system: a quantitative cineangiographic study. J Am Coll Cardiol 1986; 8: 1263-1270
    CrossrefPubMedGoogle Scholar
  • 28 Fitzgerald DJ, Roy L, Robertson RM, FitzGerald GA. The effects of organic nitrates on prostacyclin biosynthesis and platelet function in humans. Circulation 1984; 70: 297-302
    CrossrefPubMedGoogle Scholar
  • 29 Dietz Jr AJ. The biotransformation of isosorbide dinitrate in human subjects. Biochem Pharmacol 1967; 16: 2447-2452
    CrossrefPubMedGoogle Scholar
  • 30 Wendt RL. Systemic and coronary vascular effects of the 2- and the 5- mononitrate esters of isosorbide dinitrate. J Pharmacol Exp Ther 1972; 180: 732-742
    PubMedGoogle Scholar
  • 31 Best LC, Martin TJ, Russel RG G, Preston FE. Prostacyclin increases cyclic AMP levels and adenylate cyclase activity in platelets. Nature 1977; 267: 850-852
    CrossrefPubMedGoogle Scholar
  • 32 Katsuki S, Arnold W, Mittal C, Murad F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cycl Nucleot Res 1977; 3: 23-35
    PubMedGoogle Scholar
  • 33 Galvas PE, Di Salvo J. Concentration and time-dependent relationship between isosorbide dinitrate-induced relaxation and formation of cyclic GMP in coronary arterial smooth muscle. J Pharmacol Exp Ther 1983; 224: 373-378
    PubMedGoogle Scholar
  • 34 Boehme E, Graf H, Schultz G. Effects of sodium nitroprusside and other smooth muscle relaxants on cyclic GMP formation in smooth muscle and platelets. Adv Cycl Nucleot Res 1978; 9: 131-143
    PubMedGoogle Scholar
  • 35 Scalzo Lo. N-acetyl-cysteine potentiates inhibition of platelet aggregation by nitroglycerin. J Clin Invest 1985; 76: 703-708
    CrossrefPubMedGoogle Scholar