Mental stress often causes myocardial ischemia in patients with coronary artery disease (CAD). There is increasing evidence that the coronary microcirculation of patients with atherosclerosis may be dysfunctional, with the potential of contributing to myocardial ischemia. This study investigated sympathetically mediated coronary microcirculatory and regional noradrenergic effects of mental stress. We measured left anterior descending coronary artery blood flow and norepinephrine kinetics at rest and during a 10-minute video game in 10 CAD patients with nonsignificant atherosclerosis of this artery and in 5 patients with normal coronary angiograms (NCA). The 2 groups did not differ in their responses of systemic and cardiac norepinephrine spillovers, heart rate, and blood pressure during mental stress. Patients with NCA had microvascular dilation during mental stress (26 +/- 9% [mean +/- SD] decline in coronary vascular resistance from baseline, p < 0.01), whereas patients with CAD did not (9 +/- 20% decline, p = 0.11). Six patients with CAD then received intracoronary phentolamine (1.7 micrograms/kg/min for 5 minutes, followed by 0.17 micrograms/kg/min) and played the video game again. In contrast to nonsignificant changes in coronary resistance during the initial video game (6 +/- 15% decline, p = 0.20), coronary vascular resistance decreased significantly during the repeat video game (25 +/- 19% decline, p = 0.02). Vasomotor responses of epicardial coronary artery segments did not differ between the 2 video game studies. Five other patients (4 with CAD, 1 with NCA) repeated the video game during intracoronary administration of 5% dextrose, with systemic and coronary hemodynamic and noradrenergic responses unchanged from those during the initial video game.(ABSTRACT TRUNCATED AT 250 WORDS)