Download PDF
Thromb Haemost 2000; 83(02): 309-315
DOI: 10.1055/s-0037-1613804
Rapid Communication
Schattauer GmbH

Randomized, Placebo-controlled, Blinded and Cross-matched Study on the Antiplatelet Effect of Inhaled Nitric Oxide in Healthy Volunteers

André Gries
,
Axel Herr
,
Johann Motsch
,
Alexandra Holzmann
,
Jörg Weimann
,
Friedemann Taut
,
Natalie Erbe
1   German Cancer Research Center, University of Heidelberg, Germany
,
Christoph Bode
2   Department of Cardiology, University of Freiburg, Germany
,
Eike Martin
› Author Affiliations
Further Information

Publication History

Received 03 June 1999

Accepted after revision 10 October 1999

Publication Date:
11 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

The platelet inhibitory effect of 0-40 ppm inhaled nitric oxide (NO) was investigated in healthy men and women. In both groups, ADPand collagen-induced platelet aggregation was significantly inhibited 20 (T20) and 40 min (T40) after the beginning of inhalation of 5, 10, and 40 ppm. Moreover, in both men and women, the in vitro bleeding time was significantly prolonged at T20 and T40 during inhalation of 40 ppm. Inhalation of NO also inhibited P-selectin expression at 5, 10, and 40 ppm and fibrinogen binding to the GPIIb/IIIa-receptor at 40 ppm. In conclusion, in healthy volunteers, the platelet inhibitory effect of inhaled NO was not dose-related, since it was significant at 5 and 10 ppm but did not increase during the administration of higher NO concentrations. In addition, gender-related differences were only observed in ADP-induced platelet aggregation at 10 ppm and in bleeding time prolongation at 40 ppm.

Keywords

Platelets - aggregation - bleeding time - P-selectin expression - fibrinogen binding - inhaled nitric oxide

* Presented in part at the German Congress of Anesthesiology, Frankfurt, Germany, July 4 1998.


** Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG; GR1765/1-2).


 

  • References

  • 1 Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide in adult respiratory distress syndrome. N Engl J Med 1993; 328: 399-405.
    CrossrefPubMedGoogle Scholar
  • 2 Pearl RG. Inhaled nitric oxide. The past, the present, and the future. Anesthesiology 1993; 78: 413-6.
    PubMedGoogle Scholar
  • 3 Högman M, Frostell C, Arnberg H, Sandhagen B, Hedenstierna G. Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiol Scand 1994; 151: 125-9.
    CrossrefPubMedGoogle Scholar
  • 4 Högman M, Frostell C, Arnberg H, Hedenstierna G. Bleeding time prolongation and NO inhalation (letter). Lancet 1993; 341: 1664-5.
    PubMedGoogle Scholar
  • 5 Gries A, Böttiger BW, Dörsam J, Bauer H, Weimann J, Bode C, Martin E, Motsch J. Inhaled nitric oxide inhibits platelet aggregation following pulmonary embolism in pigs. Anesthesiology 1997; 86: 387-93.
    CrossrefPubMedGoogle Scholar
  • 6 Samama CM, Diaby M, Fellahi JL, Mdhafar A, Eyraud D, Arock M, Guillosson JJ, Coriat P, Rouby JJ. Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 1995; 83: 56-65.
    CrossrefPubMedGoogle Scholar
  • 7 Radomski MW, Palmer RMJ, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol 1987; 92: 181-7.
    CrossrefPubMedGoogle Scholar
  • 8 Amano M, Takahashi M, Kosaka T, Kinoshita M. Differential inhibition of platelet aggregation and calcium mobilization by nitroglycerin and stabilized nitric oxide. J Cardiovasc Pharmacol 1994; 24: 860-6.
    CrossrefPubMedGoogle Scholar
  • 9 Karlberg KE, Torfgard K, Ahlner J, Sylvén C. Dose-dependent effect of intravenous nitroglycerin on platelet aggregation, and correlation with plasma glyceryl dinitrate concentration in healthy men. Am J Cardiol 1992; 69: 802-5.
    CrossrefPubMedGoogle Scholar
  • 10 Harris SN, Rinder CS, Rinder HM, Tracey JB, Smith BR, Hines R. Nitroprusside inhibition of platelet function is transient and reversible by catecholamine priming. Anesthesiology 1995; 83: 1145-52.
    CrossrefPubMedGoogle Scholar
  • 11 Gries A, Bode C, Peter KH, Herr A, Böhrer H, Motsch J, Martin E. Inhaled nitric oxide inhibits human platelet aggregation, P-selectin expression, and fibrinogen binding in vitro and in vivo. Circulation 1998; 97: 1481-7.
    CrossrefPubMedGoogle Scholar
  • 12 Albert J, Wallen NH, Broijersen A, Frostell C, Hjemdahl P. Effects of inhaled nitric oxide compared with aspirin on platelet function in vivo in healthy subjects. Clin Sci Colch 1996; 91: 225-31.
    CrossrefPubMedGoogle Scholar
  • 13 Kharitonov SA, Logan-Sinclair RB, Busset CM, Shinebourne EA. Peak expiratory nitric oxide differences in men and women: relation to the menstrual cycle. Br Heart J 1994; 72: 243-5.
    CrossrefPubMedGoogle Scholar
  • 14 Barber DA, Miller VM. Gender differences in endothelium-dependent relaxations do not involve NO in porcine coronary arteries. Am J Physiol 1997; 273: H2325-32.
    PubMedGoogle Scholar
  • 15 Chowienczyk PJ, Watts GF, Cockcroft JR, Brett SE, Ritter JM. Sex differences in endothelial function in normal and hypercholesterolaemic subjects. Lancet 1994; 344: 305-6.
    CrossrefPubMedGoogle Scholar
  • 16 Gries A, Motsch J, Penk S, Bauer H, Weimann J, Martin E. Sex-dependent differences in bleeding time prolongation under inhaled nitric oxide (abstract). Br J Anaesth 1995; 74 Suppl I 124.
    PubMedGoogle Scholar
  • 17 Andrews NP, Gralnick HR, Merryman P, Vail M, Quyyumi AA. Mechanisms underlying the morning increase in platelet aggregation: a flow cytometry study. J Am Coll Cardiol 1996; 28: 1789-95.
    CrossrefPubMedGoogle Scholar
  • 18 Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-9.
    PubMedGoogle Scholar
  • 19 Kratzer MAA, Born GVR. Simulation of primary hemostasis in vitro. Hemostasis 1985; 15: 357-62.
    PubMedGoogle Scholar
  • 20 Langford EJ, Wainwright RJ, Martin JF. Platelet activation in acute myocardial infarction and unstable angina is inhibited by nitric oxide donors. Arterioscler Thromb Vasc Biol 1996; 16: 51-5.
    CrossrefPubMedGoogle Scholar
  • 21 Oudkerk MPool, Bouma G, Visser JJ, Kolkman JJ, Tran DD, Meuwissen SG, Pena AS. Serum nitrate levels in ulcerative colitis and Crohn’s disease. Scand J Gastroenterol 1995; 30: 784-8.
    CrossrefPubMedGoogle Scholar
  • 22 De Graaf JC, Banga JD, Moncada S, Palmer RMJ, de Groot PG, Sixma JJ. Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation 1992; 85: 2284-90.
    CrossrefPubMedGoogle Scholar
  • 23 Loscalzo J. Antiplatelet and antithrombotic effects of organic nitrates. Am J Cardiol 1992; 70: 18B-22B.
    CrossrefPubMedGoogle Scholar
  • 24 Moncada S, Palmer MJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharm Rev 1991; 43: 108-42.
    PubMedGoogle Scholar
  • 25 Werns SW, Rote WE, Davis JH, Guevara T, Lucchesi BR. Nitroglycerin inhibits experimental thrombosis and reocclusion after thrombolysis. Am Heart J 1994; 127: 727-37.
    CrossrefPubMedGoogle Scholar
  • 26 Michelson AD, Benoit SE, Furman MI, Breckwoldt WL, Rohrer MJ, Barnard MR, Loscalzo J. Effects of nitric oxide/EDRF on platelet surface glycoproteins. Am J Physiol 1996; 270: H1640-8.
    PubMedGoogle Scholar
  • 27 Kermarrec N, Zunic P, Beloucif S, Benessiano J, Drouet L, Payen D. Impact of inhaled nitric oxide on platelet aggregation and fibrinolysis in rats with endotoxic lung injury. Role of cyclic guanosine 5’-monophosphate. Am J Respir Crit Care Med 1998; 158: 833-9.
    CrossrefPubMedGoogle Scholar
  • 28 Breuer J, Leube G, Mayer P, Gebhardt S, Sieverding L, Haberle L, Heinemann M, Apitz J. Effects of cardiopulmonary bypass and inhaled nitric oxide on platelets in children with congenital heart defects. Eur J Pediatr 1998; 157: 194-201.
    CrossrefPubMedGoogle Scholar
  • 29 Young JD, Sear JW, Valvini EM. Kinetics of methaemoglobin and serum nitrogen oxide production during inhalation of nitric oxide in volunteers. Br J Anaesth 1996; 76: 652-6.
    CrossrefPubMedGoogle Scholar
  • 30 Adrie C, Bloch KD, Moreno PR, Hurford WE, Guerrero JL, Holt R, Zapol WM, Gold HK, Semigran MJ. Inhaled nitric oxide increases coronary artery patency after thrombolysis. Circulation 1996; 94: 1919-26.
    CrossrefPubMedGoogle Scholar
  • 31 Lee JS, Adrie C, Jacob HJ, Roberts Jr JD, Zapol WM, Bloch KD. Chronic inhalation of nitric oxide inhibits neointimal formation after ballooninduced arterial injury. Circ Res 1996; 78: 337-42.
    CrossrefPubMedGoogle Scholar
  • 32 George TN, Johnson KJ, Bates JN, Segar JL. The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates. J Pediatr 1998; 132: 731-4.
    CrossrefPubMedGoogle Scholar
  • 33 Langford EJ, Brown AS, Wainwright RJ, de Belder AJ, Thomas MR, Smith REA, Martin JF, Moncada S. Inhibition of platelet activity by S-nitrosoglutathione during coronary angioplasty. Lancet 1994; 344: 1458-60.
    CrossrefPubMedGoogle Scholar
  • 34 Christou H, Magnani B, Morse DS, Allred EN, Van Marter LJ, Wessel DL, Kourembanas S. Inhaled nitric oxide does not affect adenosine 5’-diphosphate-dependent platelet activation in infants with persistent pulmonary hypertension of the newborn. Pediatrics 1998; 102: 1390-3.
    CrossrefPubMedGoogle Scholar
  • 35 Emery JD, Leifer DW, Moura GL, Southern P, Morrissey JH, Lawrence JB. Whole-blood platelet aggregation predicts in vitro and in vivo primary hemostatic function in the elderly. Arterioscler Thromb Vasc Biol 1995; 15: 748-53.
    CrossrefPubMedGoogle Scholar
  • 36 Dellinger RP, Zimmermann JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis jr K, Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled nitric oxide in ARDS study group. Crit Care Med 1998; 26: 15-23.
    CrossrefPubMedGoogle Scholar
  • 37 Germann P, Ziesche R, Leitner C, Roeder G, Urak G, Zimpfer M, Sladen R. Addition of nitric oxide to oxygen improves cardiopulmonary function in patients with severe COPD. Chest 1998; 114: 29-35.
    CrossrefPubMedGoogle Scholar
  • 38 Lu Q, Mourgeon E, Law-Koune JD, Roche S, Vezinet C, Abdennour L, Vicaut E, Puybasset L, Diaby M, Coriat P, Rouby JJ. Dose-response curves of inhaled nitric oxide with and without intravenous almitrine in nitric oxide-responding patients with acute respiratory distress syndrome. Anesthesiology 1995; 83: 929-43.
    CrossrefPubMedGoogle Scholar
  • 39 Hayashi T, Fukoto JM, Ignarro LJ, Chaudhuri G. Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implication for artherosclerosis. Proc Natl Acad Sci USA 1992; 89: 11259-63.
    CrossrefPubMedGoogle Scholar
  • 40 Beisiegel B, Treese N, Hafner G, Meyer J, Darius H. Increase in endogenous fibrinolysis and platelet activity during exercise in young volunteers. Agents Action Suppl 1992; 37: 183-9.
    PubMedGoogle Scholar
  • 41 Stohlawetz P, Hergovich N, Stiegler G, Eichler HG, Hocker P, Kapiotis S, Jilma B. Differential induction of P-selectin expression on platelets by two cell separators during plateletpheresis and the effect of gender on the release of soluble P-selectin. Transfusion 1998; 38: 24-30.
    CrossrefPubMedGoogle Scholar
  • 42 Faraday N, Goldschmidt-Clermont PJ, Bray PF. Gender differences in platelet GPIIb-IIIa activation. Thromb Haemost 1997; 77: 748-54.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Freedman JE, Ting B, Hankin B, Loscalzo J, Keaney jr JF, Vita JA. Impaired platelet production of nitric oxide predicts presence of acute coronary syndromes. Circulation 1998; 98: 1481-6.
    CrossrefPubMedGoogle Scholar
  • 44 Lindemann S, Klingel B, Fisch A, Meyer J, Darius H. Increased platelet sesitivity toward platelet inhibitors during physical exercise in patients with coronary artery disease. Thromb Res 1999; 93: 51-9.
    CrossrefPubMedGoogle Scholar
  • 45 Bando K, Vijayaraghavan P, Turrentine MW, Sharp TG, Ensing GJ, Sekine Y, Szekely L, Morelock RJ, Brown JW. Dynamic changes of endothelin-1, nitric oxide, and cyclic GMP in patients with congenital heart disease. Circulation 1997; 96: II-346-51.
    PubMedGoogle Scholar
  • 46 Malmros C, Blomquist S, Dahm P, Martensson L, Thörne J. Nitric oxide inhalation decreases pulmonary platelet and neutrophil sequestration during extracorporeal circulation in the pig. Crit Care Med 1996; 24: 845-9.
    CrossrefPubMedGoogle Scholar
  • 47 Vallance P, Benjamin N, Collier J. The effect of endothelium-derived nitric oxide on ex vivo whole blood aggregation in man. Eur J Clin Pharmacol 1992; 42: 37-41.
    CrossrefPubMedGoogle Scholar
  • 48 Tanus-Santos JE, Moreno jr H, Zappellini A, de Nucci G. Small-dose inhaled nitric oxide attenuates hemodynamic changes after pulmonary air embolism in dogs. Anesth Analg 1999; 88: 1025-9.
    CrossrefPubMedGoogle Scholar
  • 49 Moreno H, Tanus-Santos JE. Nitric oxide inhalation during massive pulmonary embolism (letter). Anesth Analg 1999; 88: 1188.
    CrossrefPubMedGoogle Scholar