This study reports coronary and systemic hemodynamics, and metabolic responses to atrial pacing, prostacyclin (PGI₂), and lioprost, its stable analogue, in 16 patients with severe coronary obstruction as well as predominant narrowing in the left anterior descending artery. PGI₂ caused ischemia in six patients with low anginal threshold during pacing. In three of them ischemia was also precipitated by iloprost. Drugs were infused at therapeutic doses and were discontinued when pain occurred. Angina disappeared promptly (≤ 3 minutes) and spontaneously after the infusion of PGI₂, whereas after the analogue it was long lasting (≥ 5 minutes) and was relieved by 125 mg intravenous aminophylline, an antagonist of dipyridamole-induced coronary dilation. Ischemia was associated with a drug-induced decrease in arterial blood pressure and reflex tachycardia, and occurred despite increased great cardiac vein (GCV) blood flow and decreased resistance, which is consistent with either a failure of regional flow to increase proportionally to the metabolic demand or a subendocardial-subepicardial steal. However, the following findings favor the latter hypothesis: (1) heart rate and rate-pressure product at the onset of pain were lower with drugs than with pacing, and (2) GCV blood flow, measured at a comparable heart rate, was less with pacing than with drugs. In conclusion, PGI₂ and analogues may induce ischemia in patients with advanced coronary artery disease. The mechanism appears to be related to a dipyridamole-like maldistribution of flow. Counteraction of ischemia can be achieved by aminophylline.