Partial inhibition of nitric oxide synthase primes the stimulated pathway of vWF-secretion in man.
Increased release of von Willebrand factor (vWF) has been linked to the pathogenesis of atherosclerosis. For this complex disease, impairment of endothelium-derived, nitric oxide production and impaired vascular relaxation has also been reported. Since endothelially produced nitric oxide (NO) is known to inhibit secretion of the Weibel-Palade bodies in animals, we hypothesized that NO could mitigate vWF secretion. In a randomized, placebo controlled cross-over trial, eight male volunteers received N-monomethyl-L-arginine (LNMMA) to block endothelial NO production or placebo, and vWF release was stimulated by infusing desmopressin in three cumulative doses (0.05, 0.15, 0.4 microg/kg) in both periods. At a threshold dose of 0.l5 microg/kg desmopressin, concomitant partial blockade of NO production resulted in 20% higher levels of vWF (P<0.04). However, maximal vWF release after 0.4 microg/kg desmopressin was unaffected by L-NMMA (Delta7% between periods, P=0.88). These data show the dampening effect of NO production on vWF release in response to threshold concentrations of secretagogues. This may in part explain the higher vWF levels in cardiovascular diseases associated with impaired endothelial NO generation.
Pernerstorfer
T
T
Department for Clinical Pharmacology, Vienna University Medical School, Vienna, Austria. thomas.pernerstorfer@univie.ac.at
Stohlawetz
P
P
Kapiotis
S
S
Eichler
H G
HG
Jilma
B
B
D000328:Adult; D018592:Cross-Over Studies; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D009000:Monocytes / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012119:Respiration; D019323:omega-N-Methylarginine / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism*
D004791:Enzyme Inhibitors; D014841:von Willebrand Factor; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D003894:Deamino Arginine Vasopressin