An intracoronary drug infusion protocol was employed to assess the hemodynamic effects of synthetic atrial natriuretic peptide in normal subjects and to evaluate its actions on epicardial coronary artery dimensions. Increasing concentrations of synthetic atrial natriuretic peptide (1.75 to 84 μg/min) were infused at a constant rate directly into the left coronary artery in eight patients with normal left ventricular function and left coronary artery angiograms. Steady-state hemodynamic parameters and high-fidelity left ventricular pressure were recorded at each dose and indexes of left ventricular contractile and diastolic function were calculated. Coronary angiograms obtained at baseline and the highest dose of atrial natriuretic peptide were compared by quantitative image analysis techniques. At the highest dose administered, atrial natriuretic peptide decreased mean pulmonary artery pressure (− 36%, p< 0.01), pulmonary capillary wedge pressure (− 80%, p< 0.01), left ventricular end-diastolic pressure (− 58%, p< 0.01), left ventricular end-systolic pressure (− 11%, p< 0.01), mean arterial pressure (− 8%, p< 0.05), and pulmonary vascular resistance (− 18%, p< 0.05). Cardiac output and systemic vascular resistance were unchanged, and heart rate and peak positive dP dt increased. Peak negative dP dt and the time constant of early diastolic relaxation calculated by the logarithmic method both fell at the highest dose of atrial natriuretic peptide, although the time constants calculated by other less load-sensitive methods were unchanged. Doses of intracoronary atrial peptide that did not alter left ventricular load had no effect on indexes of left ventricular systolic or diastolic function despite a presumably high intramyocardial concentration of the agent. Epicardial coronary artery diameter and calculated cross-sectional area were measured in 40 segments of the left anterior descending and left circumflex coronary arteries in eight subjects before and after atrial peptide administration. Mean coronary diameter increased 27%, from 2.05±0.19 to 2.61±0.21 mm (p= 0.0001), in the left anterior descending artery and increased 26%, from 2.11±0.16 to 2.65±0.18 mm (p= 0.0001), in the left circumflex artery; cross-sectional area increased an average of 54±11%(p< 0.001). There were no side effects related to atrial peptide administration. These results indicate that in normal subjects atrial natriuretic peptide lowers blood pressure without direct myocardial effects and dilates epicardial coronary arteries.