A group of patients has been described who have chest pain resembling angina and positive exercise tests, but normal coronary angiograms and no coronary-artery spasm. This constellation of features has sometimes been called syndrome X or microvascular angina. We attempted to determine whether endothelium-dependent vasodilatation of the coronary vasculature was impaired in patients with this syndrome. We infused the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilators papaverine and isosorbide dinitrate into the left coronary artery of 9 patients and 10 control subjects. The diameter of the left anterior descending coronary artery was assessed by quantitative angiography, and changes in coronary blood flow were estimated with the use of an intracoronary Doppler catheter. Acetylcholine, given in doses of 1, 3, 10, and 30 micrograms per minute, increased coronary blood flow in a dose-dependent manner in both groups. However, the mean (+/- SD) acetylcholine-induced increases in coronary blood flow were significantly less (P < 0.001) in the patient (8 +/- 14, 37 +/- 37, 59 +/- 67, and 103 +/- 77 percent, respectively) than in the controls (62 +/- 52, 186 +/- 93, 341 +/- 128, and 345 +/- 78 percent, respectively). The changes in coronary blood flow in response to 2 mg of isosorbide dinitrate (236 +/- 66 percent vs. 280 +/- 56 percent) and 10 mg of papaverine (366 +/- 168 percent vs. 411 +/- 92 percent) did not differ significantly between the patients and controls. The administration of papaverine resulted in myocardial lactate production in the patients but not in the controls. The three lower doses of acetylcholine caused a similar degree of dilatation of the left anterior descending coronary artery in the two groups, and the highest dose caused a similar degree of constriction in the two groups. Isosorbide dinitrate and papaverine caused a similar degree of dilatation in both groups. These findings suggest that endothelium-dependent dilatation of the resistance coronary arteries is defective in patients with anginal chest pain and normal coronary arteries, which may contribute to the altered regulation of myocardial perfusion in these patients.