In the peripheral vasculature, insulin induces time- and dose-dependent vasodilation. We have recently demonstrated that insulin potentiates adenosine-stimulated myocardial blood flow. However, it is unknown whether insulin's effects on the coronary vasculature are dose dependent. In this study, we quantitated myocardial blood flow and adenosine-stimulated coronary flow (140 microg.kg(-1).min(-1) for 5 min) in 10 healthy men (age, 32 +/- 6 years; BMI, 24.1 +/- 1.8 kg/m(2)) using positron emission tomography and (15)O-labeled water. Hyperemic myocardial blood flow was measured in the basal state, during euglycemic physiological hyperinsulinemia (serum insulin approximately 65 mU/l) and during supraphysiological hyperinsulinemia (serum insulin approximately 460 mU/l). Basal myocardial blood flow was 0.84 +/- 0.17 ml.g(-1).min(-1). Physiological hyperinsulinemia increased the adenosine-stimulated flow by 20% (from 3.92 +/- 1.17 to 4.72 +/- 0.96 ml.g(- 1).min(-1); P < 0.05). Supraphysiological hyperinsulinemia further enhanced the adenosine-stimulated flow by 19% (to 5.61 +/- 1.03 ml.g(-1).min(-1); P < 0.05). These effects were not explained by changes in systemic hemodynamics, since coronary resistance decreased during each insulin infusion (P < 0.05). In addition, hyperemic myocardial blood flow responses during insulin stimulation were positively correlated with whole-body glucose uptake. The results demonstrate that insulin is able to enhance hyperemic myocardial blood flow in a dose-dependent manner in healthy subjects. These effects might contribute to the known beneficial dose-dependent effects of insulin on myocardial ischemia.