Considerable evidence suggests that coronary endothelium regulates myocardial blood flow and metabolism by elaborating vasoactive substances. The physiologic signals mediating this process are uncertain. To test the hypothesis that the process is influenced by physiologic variation in local insulin concentration, we examined the effect of direct intracoronary insulin infusion on myocardial blood flow and oxidative substrate metabolism in 10 patients with coronary heart disease. Ten men (aged 51 to 68 years) who were fasting received a 60-minute intracoronary infusion of insulin at a rate (10 mU/min) sufficient to raise coronary venous plasma insulin from 12+/-4 to 133+/-17 mU/ml without increasing the systemic insulin level. Local coronary hyperinsulinemia increased coronary sinus blood flow in every subject, from 50+/-4 to 61+/-6 ml/min (p<0.01). Insulin also increased myocardial uptake of glucose (from 6+/-1 to 17+/-6 mmol/min) and lactate (from 8+/-2 to 12+/-5 mmol/min), resulting in approximately 30% increase in total oxidative substrate uptake, but without increasing myocardial oxygen consumption (7.0+/-0.7 vs. 7.1+/-0.8 ml/min). Thus, physiologic elevation in the local plasma insulin concentration increases coronary blood flow in the absence of any increase in myocardial oxygen demand or consumption, suggesting a primary reduction in coronary tone, while simultaneously restraining the oxidation of imported substrates. These observations are consistent with insulin-mediated elaboration of vasoactive and/or paracrine factors within the coronary circulation.