EFFECTS OF HISTAMINE AND NITRIC-OXIDE SYNTHASE INHIBITION ON PLASMA-LEVELS OF VON-WILLEBRAND-FACTOR ANTIGEN

Endothelial cells release von Willebrand factor (vWf) either constitut ively or by a regulated pathway, Based on various studies in vitro, we hypothesized that the stimulatory action of histamine on vWf release could also be induced in vivo and that it may be inhibited by endogeno us production of nitric oxide (NO). Nine healthy subjects received pla cebo or one of two dosages of a primed constant infusion of the NO-syn thase inhibitor N-monomethyl-L-arginine (L-NMMA) in a randomized, doub le-blind, three-way crossover trial. Histamine was coinfused for 15 mi nutes at 0.16 mu g/kg/min after 30 minutes of pretreatment with either placebo or L-NMMA. Thirty minutes after either the low or the high L- NMMA dose was started, which caused, respectively, a 40% decrease and a 60% decrease in exhaled end expiratory NO level (p = 0.008), there w as no increase in von Willebrand factor antigen (vWf-Ag) level (p > 0. 05). Histamine caused an 11% (95% confidence interval (CI): 0.4% to 22 %; p = 0.011) increase in vWf-Ag level at 125 minutes. After pretreatm ent with the low and the high L-NMMA doses, vWf-Ag level increased by 18% (CI: 5% to 31%; a = 0.011) and by 29% (CI: 15% to 42%; a = 0.008), respectively. At 125 minutes, vWf-Ag level was significantly higher a fter either L-NMMA pretreatment when compared with the results after h istamine alone (p < 0.05). In conclusion, the infusion of histamine in creased vWf-Ag level, and the inhibition of NO-synthase enhanced this effect, whereas it did not by itself elevate vWf-Ag level. Thus endoge nously produced NO may dampen the regulated pathway of vWf secretion; it will be interesting to investigate whether endogenous NO production also inhibits vWf release caused by other stimulators.