BACKGROUND: Endothelin-1 is a powerful coronary vasocontrictor that is over expressed in coronary artery disease (CAD). Adenosine is a powerful coronary vasodilator used for myocardial perfusion imaging to identify flow limiting coronary artery stenosis. Therefore, in an animal model we tested the hypotheses that intracoronary endothelin-1 may cause myocardial perfusion abnormalities by positron emission tomography (PET) at resting conditions that may persist or only partially improve after intravenous adenosine stress in the absence of myocardial scar and flow limiting stenosis. METHODS AND RESULTS: Fourteen dogs underwent serial PET perfusion imaging using Rubidium-82 before and after sub-selective intracoronary infusion of endothelin-1, followed by intravenous and then intracoronary adenosine. Small physiologic doses of endothelin-1 infused into the mid Left Circumflex Coronary Artery caused quantitatively significant resting perfusion abnormalities that normalized after intracoronary adenosine but not consistently after intravenous adenosine used for diagnostic imaging. After effects of adenosine abated, resting perfusion defects returned, lasting up to 5 hours in some animals. Cumulative doses of endothelin-1 caused perfusion defects that did not normalize after intravenous adenosine. CONCLUSION: In an animal model without myocardial scar or flow limiting stenosis, intracoronary endothelin-1 causes visually apparent, quantitatively significant, long lasting myocardial perfusion defects at resting conditions that may persist or only partially improve after intravenous adenosine used for diagnostic imaging. These results may potentially explain resting perfusion abnormalities or heterogeneity by clinical PET that may persist or only partially improve after adenosine stress perfusion imaging in the absence of myocardial scar and flow limiting stenosis.