Syndrome X may be caused by a coronary microvascular dysfunction, possibly due to abnormalities in coronary endothelial function. Previous studies suggested that endothelin-1 (ET-1) might be involved in the pathogenesis of syndrome X. Baseline arterial and coronary sinus ET-1 levels were measured in 13 patients with syndrome X (10 women, 52+/-7 years) and in 8 control patients (5 women, 46+/-11 years). ET-1 was also measured after atrial pacing in 12 patients with syndrome X and all controls. To simultaneously assess the activity of nitric oxide, guanosine 3'-5'-cyclic monophosphate (cGMP) was also measured in 11 patients with syndrome X and 7 controls. Baseline arterial (2.27+/-0.46 vs. 1.90+/-0.22 pg/ml, p<0.05) and coronary sinus (2.03+/-0.43 vs. 1.68+/-0.28 pg/ml, p = 0.06) ET-1 plasma levels were higher in patients than in controls. After pacing, arterial ET-1 levels did not change in either group and coronary sinus ET-1 levels were also unchanged in controls. In contrast, coronary sinus ET-increased significantly in response to atrial pacing in patients with syndrome X (p = 0.023), and differences between coronary sinus ET-1 levels of patients with syndrome X and controls after pacing became highly significant (2.22+/-0.45 vs. 1.69+/-0.20 pg/ml, respectively, p = 0.006). No significant differences in arterial and coronary sinus cGMP concentrations were found between the 2 groups, both at baseline and after pacing. Our findings suggest that an increased vasoconstrictor activity of microvascular endothelium is present in at least some patients with syndrome X and may be involved in the pathogenesis of the syndrome.