The mechanism for the therapeutic effect of nitroglycerin in stress-induced angina remains controversial; it has been attributed to both increased blood supply to the ischemic myocardium and decreased myocardial oxygen demand. To investigate the contribution of each of these mechanisms, systemic pressures and great cardiac vein flow were measured in 14 patients with single-vessel disease involving the left anterior descending (LAD) coronary artery during the development of pacing-induced angina and after the administration of nitroglycerin while continuing pacing at the angina-provoking rate. Great cardiac vein flow, measured by thermodilution, represents the venous efflux from the LAD territory and therefore provided an index of flow to the poststenotic myocardium. In 11 patients, nitroglycerin was administered systemically (400 to 800 micrograms sublingually or 200 micrograms intravenously); angina was relieved in 10, concomitant with a decrease in both great cardiac vein flow (from 123 +/- 29 to 98 +/- 29 ml/min, p less than 0.001) and mean aortic pressure (from 118 +/- 22 to 104 +/- 22 mm Hg, p less than 0.001). In contrast, when 75 micrograms of nitroglycerin was administered directly into the left main coronary artery of 7 patients, it produced a small increase in great cardiac vein flow (from 108 +/- 32 to 125 +/- 31 ml/min, p = 0.059), no change in aortic pressure, and no relief of angina. This study suggests that nitroglycerin's major beneficial action in pacing-induced angina is unrelated to direct effects on the coronary circulation and is likely related to its cardiac unloading effect.