Thromb Haemost 1997; 78(04): 1268-1271
DOI: 10.1055/s-0038-1657726
Rapid Communication
Schattauer GmbH Stuttgart

Partial Blockade of Nitric Oxide Synthase Blunts the Exercise-induced Increase of von Willebrand Factor Antigen and of Factor VIII in Man

Bernd Jilma
1   The Department of Clinical Pharmacology, University of Vienna, Austria
,
Eva Dirnberger
1   The Department of Clinical Pharmacology, University of Vienna, Austria
,
Hans-Georg Eichler
1   The Department of Clinical Pharmacology, University of Vienna, Austria
,
Bettina Matulla
1   The Department of Clinical Pharmacology, University of Vienna, Austria
,
Leopold Schmetterer
1   The Department of Clinical Pharmacology, University of Vienna, Austria
2   The Institute of Medical Physics, University of Vienna, Austria
,
Stylianos Kapiotis
3   The Clinical Department of Medical and Chemical Laboratory Diagnostics, Vienna University Hospital School of Medicine, Austria
,
Wolfgang Speiser
3   The Clinical Department of Medical and Chemical Laboratory Diagnostics, Vienna University Hospital School of Medicine, Austria
,
Oswald F Wagner
3   The Clinical Department of Medical and Chemical Laboratory Diagnostics, Vienna University Hospital School of Medicine, Austria
› Author Affiliations
Further Information

Publication History

Received 07 1997

Accepted after revision 02 July 1997

Publication Date:
12 July 2018 (online)

Summary

Background: Until now the effects of β-adrenergic agonists have largely been ascribed to their ability to induce intracellular formation of cyclic adenosine monophosphate. Recently evidence has been accumulating that at least some β1 and β2-adrenoceptor effects may be mediated by nitric oxide (NO). Based on these studies, we hypothesized that the β-adrenoceptor mediated increase of von Willebrand factor and factor VIII-activity (FVIII:C) in plasma during exercise, is caused by an NO-dependent mechanism. Methods: Thirteen young healthy subjects finished an exhaustive bicycle exercise protocol while they were infused placebo or the NO-synthase inhibitor N-monomethyl-L-arginine (L-NMMA) on two separate days in a randomized, double blind cross-over design. Findings: During exercise systemic haemo-dynamic changes were parallel in both treatment periods, but L-NMMA caused a partial inhibition of NO-synthase as evidenced by a 30% decrease in exhaled NO. The workload capacities were not different during L-NMMA or placebo infusion. However, under placebo treatment exercise increased vWF-Ag by a maximum of 61% (CI: 43-84; p = 0.002) and FVIII:C by 44% (CI: 31-59; p = 0.001), which was significantly attenuated when subjects were treated with L-NMMA (p <0.05): under L-NMMA treatment vWF-Ag increased by only 25% (CI: 5-51; p = 0.001) and FVIII:C by 12% (CI: 6-39; p = 0.001). Interpretation: Partial blockade of NO-synthase with L-NMMA blunts the exercise-induced increase in vWF-Ag and FVIII:C. Our trial points to a role of endogenous NO-generation in the β2-adrenergic increase in vWF/FVIII. Thus, we propose that physiologic processes which are induced by systemic β2-adrenoceptor stimulation may at least partly be mediated by NO.

 
  • References

  • 1 Groot PG, Sixma JJ. Platelet adhesion. Br J Haematol 1990; 75: 308-12
  • 2 Lip GY, Blann AD. Von Willebrand factor and its relevance to cardiovascular disorders. Br Heart J 1995; 74: 580-583
  • 3 Cash JD, Allan AG. The fibrinolytic response to moderate exercise and intravenous adrenaline in the same subjects. Br J Haematol 1967; 13: 376-383
  • 4 Corrall RJ, Webber RJ, Frier BM. Increase in coagulation factor VIII activity in man following acute hypoglycaemia: mediation via an adrenergic mechanism. Br J Haematol 1980; 44: 301-305
  • 5 Ingram GI, Knights SF, Barrow EM, Dejanov II. The rise in factor-8 concentration after infusion of adrenaline. Br J Haematol 1968; 15: 326
  • 6 Ingram GI, Jones RV. The rise in clotting factor 8 induced in man by adrenaline: effect of alpha- and beta-blockers. J Physiol Lond 1966; 187: 447-454
  • 7 Hansen JB, Wilsgard L, Olsen JO, Osterud B. Formation and persistence of procoagulant and fibrinolytic activities in circulation after strenuous physical exercise. Thromb Haemost 1990; 64: 385-389
  • 8 Kopitsky RG, Switzer ME, Williams RS, McKee PA. The basis for the increase in factor VIII procoagulant activity during exercise. Thromb Haemost 1983; 49: 53-57
  • 9 Small M, Tweddel AC, Rankin AC, Lowe GD, Prentice CR, Forbes CD. Blood coagulation and platelet function following maximal exercise: effects of beta-adrenoceptor blockade. Haemostasis 1984; 14: 262-268
  • 10 Cohen RJ, Epstein SE, Cohen LS, Dennis LH. Alterations of fibrinolysis and blood coagulation induced by exercise, and the role of beta-adrenergic-receptor stimulation. Lancet 1968; 2: 1264-1266
  • 11 Wall RT, Counts RB, Harker LA, Striker GE. Binding and release of factor VUI/von Willebrand’s factor by human endothelial cells. Br J Haematol 1980; 46: 287-298
  • 12 Tamaoki J, Chiyotani A, Kondo M, Konno K. Role of no generation in beta-adrenoceptor-mediated stimulation of rabbit airway ciliary motility. Am J Physiol 1995; 268 C 1342-1347
  • 13 Parent R, al-Obaidi M, Lavallee M. Nitric oxide formation contributes to beta-adrenergic dilation of resistance coronary vessels in conscious dogs. CircRes 1993; 73: 241-251
  • 14 Dawes M, Chowienczyk PJ, Robbins RA. Inhibition of nitric oxide (NO) synthesis in human forearm selectively inhibits β-adrenergic vasodilation. [Abstract] Circulation 1996; 94: 3053
  • 15 Krejcy K, Schmetterer L, Kastner J, Nieszpaur-Los M, Monitzer B, Schutz W, Eichler HG, Kyrle PA. Role of nitric oxide in hemostatic system activation in vivo in humans. Arterioscler Thromb Vase Biol 1995; 15: 2063-2067
  • 16 Schmetterer L, Krejcy K, Kastner J, Wolzt M, Gouya G, Findl O, Lexer F, Breiteneder H, Fercher AF, Eichler HG. The effect of systemic nitric oxide-synthase inhibition on ocular fundus pulsations in man. Exp Eye Res 1997; 64: 305-312
  • 17 Wolzt M, Schmetterer L, Ferber W, Artner E, Mensik C, Eichler HG, Krejcy K. The effect of NO-synthase inhibition on renal hemodynamics and renal function in healthy volunteers. Am J Physiol 1997; 272 (renal physiology 41): F 178-182
  • 18 Bauer JA, Wald JA, Doran S, Soda D. Endogenous nitric oxide in expired air: effects of acute exercise in humans. Life Sci 1994; 55: 1903-1909
  • 19 Gilligan DM, Panza JA, Kilcoyne CM, Waclawiw MA, Casino PR, Quyyumi AA. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 1994; 90: 2853-2858
  • 20 Jilma B, Eichler HG, Vondrovec B, Breiteneder H, Kyrle PA, Kitzweger E, Kapiotis S, Speiser W. Effects of desmopressin on circulating P-selectin. Br J Haematol 1996; 93: 432-436
  • 21 Jilma B, Kastner J, Mensik C, Vondrovec B, Hildebrandt J, Krejcy K, Wagner OF, Eichler HG. Sex differences in concentrations of exhaled nitric oxide and plasma nitrate. Life Sci 1996; 58: 469-476
  • 22 Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shineboume EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343: 133-135
  • 23 Andrew M, Carter C, O’Brodovich H, Heigenhauser G. Increases in factor VIE complex and fibrinolytic activity are dependent on exercise intensity. J Appl Physiol 1986; 60: 1917-1922
  • 24 Gastel C, van Sixma JJ, Borst-Eilers E, Leautavd M, Moes M, Plas PM, van-der Bouma BN, Sybesma JP. Preparation and infusion of cryoprecipitate from exercised donors. Br J Haematol 1973; 25: 461-466
  • 25 Speiser W, Langer W, Pschaick A, Selmayr E, Ibe B, Nowacki PE, Muller-Berghaus G. Increased blood fibrinolytic activity after physical exercise: comparative study in individuals with different sporting activities and in patients after myocardial infarction taking part in a rehabilitation sports program. Thromb Res 1988; 51: 543-555
  • 26 Matsumoto A, Hirata Y, Momomura S, Fujita H, Yao A, Sata M, Serizawa T. Increased nitric oxide production during exercise [letter]. Lancet 1994; 343: 849-850
  • 27 Murray DR, Irwin M, Rearden CA, Ziegler M, Motulsky H, Maisel AS. Sympathetic and immune interactions during dynamic exercise, mediation via a β2-adrenergic-dependent mechanism. Circulation 1992; 86: 203-213