Partial blockade of nitric oxide synthase blunts the exercise-induced increase of von Willebrand factor antigen and of factor VIII in man.
BACKGROUND
Until now the effects of beta-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 beta1 and beta2-adrenoceptor effects may be mediated by nitric oxide (NO). Based on these studies, we hypothesized that the beta-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.


RESULTS
During exercise systemic haemodynamic 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).


CONCLUSIONS
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 beta2-adrenergic increase in vWF/FVIII. Thus, we propose that physiologic processes which are induced by systemic beta2-adrenoceptor stimulation may at least partly be mediated by NO.
Jilma
B
B
Department of Clinical Pharmacology, University of Vienna, Austria.
Dirnberger
E
E
Eichler
H G
HG
Matulla
B
B
Schmetterer
L
L
Kapiotis
S
S
Speiser
W
W
Wagner
O F
OF
D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005169:Factor VIII / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D005082:Physical Exertion / Q000502:physiology*; D011897:Random Allocation; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology*; D014841:von Willebrand Factor / Q000096:biosynthesis* / Q000235:genetics
D004791:Enzyme Inhibitors; D018343:Receptors, Adrenergic, beta-2; D014841:von Willebrand Factor; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D005169:Factor VIII; D019001:Nitric Oxide Synthase