This study evaluated both cardiac hemodynamic and metabolic effects of a graded intracoronary artery infusion of insulin in four normal and five obese anesthetized dogs. Dogs were anesthetized with isoflurane, a catheter was advanced under fluoroscopic guidance into the coronary sinus and great cardiac vein, and a 20-MHz 3F coronary Doppler catheter was advanced into either the mid left anterior descending or circumflex coronary artery. A graded intracoronary insulin infusion was administered (starting at 0.3 mU/min and doubling every 40 minutes until a maximum dose of 2.4 mU/min was achieved). Coronary glucose extraction, coronary blood flow velocity, and coronary artery size were measured at each infusion rate. An intracoronary artery infusion of insulin stimulated myocardial glucose uptake in normal dogs. However, in high-fat-fed dogs, weight gain was associated with a reduction in the ability of insulin to promote glucose uptake by cardiac muscle and a rightward shift in the dose-response curve. In normal dogs, an intracoronary insulin infusion resulted in an increase in coronary blood flow and coronary vasodilation (with insulin coronary vascular resistance index decreases to 0.72 +/- 0.06, P<.01), whereas with weight gain the vasodilator response to insulin was lost. The loss of coronary artery vasodilation to local hyperinsulinemia in fat-fed dogs is consistent with other reports in obese or hypertensive humans that document an impairment in the action of insulin to increase skeletal muscle blood flow.