At low energy density (0.03 mJ/mm2), extracorporeal shock waves (ESW), originally developed for clinical lithotripsy, have successfully been used for anti-inflammatory treatment of soft tissues. Since nitric oxide plays a critical role in inflammation, we hypothesized for ESW to increase NO production in cells. Using human umbilical vein endothelial cells as a model system, we observed that ESW, at low energy density, rapidly induced an enhancement of eNOS activity. In these cells, eNOS activity is modulated by tyrosine- and serine-phosphorylation. ESW shifted eNOS to a less-tyrosine-phosphorylated form, without affecting its serine-phosphorylation, thus accounting for its rapid enzyme activation. LPS/IFN-gamma treatment of human umbilical vein endothelial cells induced a rapid inhibition of eNOS activity and concomitant NF-kappaB activation which were efficiently counteracted by ESW treatment. Therefore, the present results indicate that the molecular mechanism of clinically observed anti-inflammatory action of ESW should include tyrosine-dephosphorylation of eNOS, a successive increase in NO production and suppression of NF-kappaB activation.