Abstract OBJECTIVES We compared the effects of intrapericardial and intracoronary nitroglycerin on coronary cross-sectional area as assessed by intravascular ultrasound and demonstrated the feasibility of local cardiac drug delivery by a newly developed method to access the normal pericardial space through the right atrial appendage. BACKGROUND Studies of nitric oxide (NO) donors have suggested that their antiarrhythmic and antiproliferative properties are more effective when administered by the intrapericardial rather than intravascular route. We postulated that NO donors delivered intrapericardially would also cause sustained coronary vasodilation without significant systemic hypotension. METHODS Intrapericardial nitroglycerin (200 μg) was administered in five Yorkshire pigs. Coronary cross-sectional luminal area was measured with intravascular ultrasound at various time intervals. The effects of intracoronary nitroglycerin on coronary luminal area were used for comparison. RESULTS Transatrial pericardial access required 1 to 3 min in all animals. Intrapericardial nitroglycerin was associated with a mean 31.7% increase in luminal area at 5 min (p < 0.001). Vasodilation peaked between 5 and 10 min and persisted for 15 min. In contrast, intracoronary nitroglycerin was associated with a smaller mean increase in luminal area (20.3% at 5 min, p < 0.01) that disappeared by 10 min. Significant systemic hypotension was observed at 3 min with intracoronary but not with intrapericardial nitroglycerin. CONCLUSIONS Sustained coronary vasodilation can be achieved with intrapericardial delivery of nitroglycerin without systemic hypotension. Nitric oxide donors with longer half-lives could prove beneficial in the treatment of myocardial ischemic syndromes when administered through this route. Transatrial pericardial access offers a novel route for local cardiac drug delivery.