This study was designed to assess the vasomotor response of coronary arteries to exercise and the cold presser test, and its relationships with the endothelium-mediated dependent mechanism. Twenty-two patients were entered in the study. Group 1 was composed of 12 patients with a total cholesterol level <200 mg/dl associated with angiographically smooth, normal coronary arteries. Group 2 consisted of 10 patients with a cholesterol level >240 mg/dl and angiographic luminal irregularities of the left anterior descending coronary artery. Coronary blood flow was assessed by a 0.018-inch tip guidewire during Doppler ultrasonography, and analysis of the coronary arterial dimension of the midportion of the left anterior descending coronary artery was performed by quantitive coronary angiography. Catecholamine concentrations were assessed at the different stages of the protocol. The rate-pressure product increased during both the cold presser test and exercise (p <0.001). Coronary blood flow velocity increased during the cold presser and exercise tests by 24.5 +/- 10% and 72 +/- 42%, respectively (p <0.001), and by 127 +/- 62% (p <0.0001) after administration of papaverine. In group 1, the cold presser test had a more pronounced vasodilating effect on epicardial coronary arteries (+11.2 +/- 16%) compared with group 2 (-2 +/- 9%, p <0.05). Similarly, exercise had a vasodilating action in group 1 (11.3 +/- 15%)compared with group 2 (-1.9 +/- 8%, p <0.05). Both responses were highly correlated (r = 0.92, p <0.001). Papaverine administration had a vasodilating action in patients from group 1 (11.6 +/- 16%) compared with group 2 (-1.2 +/- 8%, p <0.05). Both the vasomotor responses to the cold presser test and exercise were correlated to the response to papaverine administration, r = 0.90 and r = 0.92, respectively (all p <0.001). Noradrenaline concentrations increased both during the cold pressor test and exercise (p <0.05), but not after papaverine administration. These results show that the endothelium modulates the response of epicardial coronary arteries to sympathetic stimulation, mainly by a flow-mediated mechanism.