Mental stress often causes reduced blood flow to the heart in patients with coronary artery disease. Because this response may be mediated by sympathetic activation, we assessed the impact of alpha-adrenergic blockade with phentolamine on coronary vasomotion and on cardiac and total body norepinephrine kinetics. Ten patients with coronary artery disease and 5 patients with normal coronary angiograms underwent measurements of left anterior descending coronary artery diameter, left anterior descending artery flow (derived from Doppler flow velocity measurements), and norepinephrine spillover, at rest and during 10 minutes of mental stress induced by a stressful video game. Mental stress caused constriction of large and small coronary arteries in patients with coronary artery disease, whereas these vessels dilated in patients with normal coronary angiograms. Six patients with coronary artery disease then received intracoronary phentolamine to achieve alpha-adrenergic blockade before repeating the mental stress. With phentolamine, basal cardiac norepinephrine spillover increased, whereas total body norepinephrine spillover was unchanged, indicating a local cardiac effect. Systemic hemodynamic changes were similar during both periods of mental stress. We found that alpha-adrenergic blockade with phentolamine prevented constriction of atherosclerotic coronary lesions and reduced coronary resistance during mental stress, despite an increased cardiac norepinephrine spillover. Five other patients received saline during their repeat mental stress and had similar vasomotor and norepinephrine spillover changes as during their initial mental stress study. Thus, we conclude that the coronary circulation of patients with coronary artery disease constricts during mental stress, due to alpha-adrenergic activation that may contribute to myocardial ischemia.