Background Episodic, severe coronary artery flow restriction preconditions the myocardium much like brief occlusions. The necessity for full reperfusion after a preconditioning intervention to elicit the preconditioning response is unclear. This study investigated in closed-chest swine the effect of a persistent critical coronary stenosis with moderate flow reduction on ischemic preconditioning. Methods and Results Farm pigs (n=23) assigned to one of four groups-(1) control, (2) stenosis, (3) preconditioned (PC), or (4) preconditioned plus stenosis (PC/S)-underwent percutaneous instrumentation with a percutaneous transluminal coronary angioplasty catheter advanced to the mid-left anterior descending coronary artery. An artificial coronary stenosis (82% diameter reduction) was mounted on the catheter just proximal to the balloon in the two stenosis groups. Preconditioning stimulus consisted of two 10-minute balloon occlusions followed by 15 minutes of reperfusion. All groups subsequently underwent 45 minutes of occlusion followed by 120 minutes of reperfusion. Baseline regional myocardial blood flow in the area at risk (AAR), measured with colored microspheres, was lowest in the stenosis groups, with flow expressed as a percentage of normal zone flow. Infarct size (percent of AAR), determined by staining slices of the heart with triphenyltetrazolium, was significantly reduced in PC compared with control pigs (15.1+/-5.9% versus 66.8+/-6.4%, respectively; P<.001). Infarct size in PC/S pigs was also significantly reduced (29.7+/-7.1%, P=.004 versus control) but was not different in degree from PC pigs (P=.6). The stenosis by itself conferred no preconditioning benefit (percent of AAR=69.0+/-5.4%). Conclusions A moderate flow-limiting stenosis did not pre vent preconditioning but may have attenuated the effect. This may be analogous to the clinical scenario in which intermittent coronary occlusion and reperfusion superimposed on a critical stenosis precede a prolonged occlusion treated with thrombolysis.