Effects of endothelin-1 and phenylephrine on plasma levels of von Willebrand factor and protein S

Endothelial dysfunction is considered a major factor in the pathogenesis of a wide array of diseases and often leads to increased production of, or increased responsiveness to endogenous vasoconstrictive mediators, such as endothelin-1 (ET-1) or adrenergic agonists. Based on previous studies in animals and in-vitro, we hypothesized that ET-1 and alpha adrenergic stimulation by phenylephrine (PE) may alter plasma levels of von Willebrand factor-Ag (vWF) and protein S in humans. Ten healthy men were studied in a prospective randomized double blind trial: we investigated the effects of infusions of ET-1 and PE on plasma levels of vWF-Ag and protein S. Aditionally, we examined the effects of these vasoconstrictors on thrombomodulin, tissue plasminogen activator and on protein C. ET-1 increased plasma levels of vWF-Ag by 19% (CI: 9-36%; p = 0.008) and increased plasma levels of protein-C by 7% (CI: 0.2 -12 %; p = 0.028), even at doses which produced no increase in blood pressure. Plasma levels of protein S and TPA were not significantly affected by ET-1. After PE-infusion we observed a relative increase in plasma levels of protein S by 20% (CI: 5-28%; p = 0.036) and of TPA by 14 % (CI: 2-39%; p = 0.036). Also, platelet counts increased by 36% (CI: 12-53%; p = 0.028) which correlated (r² = 0.86; p = 0.014) with an increase in leukocytes by 49 % (CI: 18-84%; p = 0.028). Plasma levels of vWF and protein C were not affected by PE and neither drug had a significant effect on plasma levels of thrombomodulin. In conclusion, our results support the study hypothesis, that ET-1 and PE increase the plasma levels of vWF and protein S, respectively. ET-1 may induce a procoagulant status in various disease states by increasing vWF-Ag levels.