BACKGROUND: Mental stress is a risk factor for atherosclerosis and may precipitate myocardial ischemia and infarction. Because endothelial dysfunction is an early manifestation of atherosclerosis, we investigated the impact of mental stress on endothelial function. Methods and Results- The effects of a 3-minute mental stress task on endothelium-dependent vasodilation were studied in healthy subjects without cardiovascular risk factors. Flow-mediated (FMD) and nitroglycerin (0.4 mg sublingual)-induced vasodilation were studied before and after mental stress by high-resolution ultrasound of the radial artery. Additionally, FMD was assessed before and 10 to 45 minutes after mental stress during intraarterial infusion of a selective endothelin A receptor antagonist (BQ-123, 1 nmol/min) or saline, respectively. Endothelium-dependent vasodilation was reduced by half for about 45 minutes (8.0+/-1.1% versus 4.1+/-1.0%; P<0.002), whereas endothelium-independent vasodilation to nitroglycerin remained unaffected (15.6+/-1.6 versus 14.3+/-1.3%; NS). Intraarterial infusion of BQ-123, a selective endothelin-A receptor antagonist, but not saline prevented the impairment of endothelium-dependent vasodilation (8.6+/-1.2 versus 9.4+/-1.3%; NS). In contrast, intraarterial infusion of norepinephrine of similar duration as mental stress did not inhibit FMD. CONCLUSIONS: Mental stress induces prolonged endothelial dysfunction, which is prevented by selective endothelin-A receptor antagonism. This represents a novel and important link between mental stress and atherosclerotic vascular disease.