The relation between isolated negative U waves and the severity of induced coronary artery spasm was investigated in 24 patients with variant angina to determine the grade of myocardial ischemia during the appearance of isolated negative U waves. Coronary artery spasm was induced by injections of either incremental doses of acetylcholine or ergonovine into the left coronary artery. Coronary spasm was quantified into 4 grades: Grade 0 = complete perfusion, Grade 1 = partial perfusion, Grade 2 = penetration without perfusion, and Grade 3 = no perfusion. Induction with acetylcholine was discontinued when a coronary spasm of Grade > or = 2 was induced. Electrocardiogram in leads V1 to V6 and systemic blood pressure were recorded continuously. Provocations of coronary spasm with at least 2 doses of acetylcholine could be performed in 15 patients. All acetylcholine-induced coronary spasms of Grade < or = 1 disappeared spontaneously within 3 min. Negative U waves developed in 19 (79%) patients, in whom 37 trials with acetylcholine or ergonovine injection were performed. Isolated negative U waves were detected in 10 trials, negative U waves and ST depression in 8 trials, and negative U waves and ST elevation in 14 trials. The induced coronary spasms associated with isolated negative U waves were of Grade 1 in 9 of the 10 trials. In contrast, all of the coronary spasms associated with negative U waves and ST elevation had a Grade of > or = 2. In conclusion, the coronary angiographic finding associated with isolated negative U waves is coronary spasm with delayed filling of the distal coronary artery, with opacification of the entire coronary bed.