The triptans, serotonin 5-HT 1B/1D agonists exemplified by sumatriptan, are an effective class of migraine therapy but have class labeling contraindicating their use in patients with coronary artery disease. Triptans have been shown to constrict human coronary artery in vitro, and there have been case reports of myocardial infarction in patients using sumatriptan. However, preclinical in vivo studies with sumatriptan in normal dogs have failed to demonstrate an effect on coronary flow. The present studies were conducted in a canine model in which regional myocardial ischemia was evoked by atrial pacing in the presence of a 40% stenosis of the left anterior descending coronary artery. Ischemic severity was quantified by changes in local epicardial electrograms (EGs) recorded in the ischemic zone. The intra-atrial administration of 10 microg x kg x min sumatriptan variably but not significantly increased the severity of regional ischemia (pre- vs. posttreatment: Delta EG: 2.00 +/- 0.17 vs. 3.05 +/- 1.15 mV). Sumatriptan at 30 microg x kg x min significantly increased ischemic severity (Delta EG: 1.88 +/- 0.19 vs. 3.32 +/- 0.58 mV, P < 0.05) concomitant with a significant reduction in coronary blood flow (8.9 +/- 0.5 vs. 7.2 +/- 0.8 mL/min, P < 0.05). These results demonstrate that a reduction in coronary flow with proischemic consequence can be modeled preclinically with sumatriptan in a canine model of cardiac stress.