Coronary artery endothelial dysfunction has been proposed as a cause of myocardial ischemia and symptoms in patients with anginal like chest pain despite normal coronary angiograms, including Syndrome X (effort chest pain, ischemic-appearing ST segment depression during exercise). We measured coronary vasomotor responses to acetylcholine (3-300 microg/min) during cardiac catheterization and systolic wall thickening responses to dobutamine (40 microg/kg/min) during transesophageal echocardiography in 42 patients (27 women, 15 men) with effort chest pain and normal coronary angiograms who also had normal electrocardiograms and echocardiograms at rest; 15 had risk factors for atherosclerosis and 12 had Syndrome X. At the dose of acetylcholine (median 100 microg/min X 2 min) that maximally increased (or minimally decreased) coronary blood flow, there was no correlation between peak coronary flow responses to acetylcholine and systolic wall thickening responses to dobutamine (r=0.100). There were no differences in the acetylcholine-stimulated epicardial coronary diameter (+5+/-13 versus +1+/-13%, p=0.386) or flow (+179+/-90 versus +169+/-96%, p=0.756) from baseline values in the 12 Syndrome X patients compared with the 30 patients with negative exercise tests. Further, there were no differences in the systolic wall thickening responses (+134+/-65 versus +118+/-57%, p=0.445) from baseline values, or in the frequency of chest pain during dobutamine infusion (100% versus 87%, p=0.308). In those patients in the lowest quartile of maximum coronary flow responses to acetylcholine (+56+/-41%), dobutamine increased systolic wall thickening by 121+/-73% from baseline values. This contractile response to dobutamine was no different than the increase in systolic wall thickening (129+/-48%, p=0.777) in patients in the highest quartile of maximum coronary flow responses (+288+/-47%). We conclude that coronary endothelial dysfunction in the absence of coronary artery disease does not cause stress-induced myocardial ischemia, regardless of the appearance of the exercise electrocardiogram, likely due to multiple mechanisms capable of appropriately dilating the coronary microcirculation during stress.