Objectives. To test whether ischemia-reperfusion alters coronary smooth muscle reactivity to vasoconstrictor stimuli such as those elicited by an adventitial stimulation with methacholine. Methods. In vitro studies were performed to assess the reactivity of endothelium-denuded infarct-related coronary arteries to methacholine (n=18). In addition, the vasoconstrictor effects of adventitial application of methacholine to left anterior descending (LAD) coronary artery was assessed in vivo in pigs submitted to 2h of LAD occlusion followed by reperfusion (n=12), LAD deendothelization (n=11), or a sham operation (n=6). Endothelial-dependent vasodilator capacity of infarct-related LAD was assessed by intracoronary injection of bradykinin (n=13). Results. In vitro, smooth muscle reactivity to methacholine was unaffected by ischemia-reperfusion. In vivo, baseline methacholine administration induced a transient and reversible drop in coronary blood flow (9.6±4.6 to 1.9±2.6 mL/min, p<0.01), accompanied by severe LV dysfunction. After ischemia-reperfusion, methacholine induced a prolonged and severe coronary blood flow drop (9.7±7.0 to 3.4±3.9 mL/min), with a significant delay in recovery (p<0.001). Endothelial denudation mimics in part the effects of methacholine after ischemia-reperfusion, and intracoronary bradykinin confirmed the existence of endothelial dysfunction. Conclusions. Infarct-related epicardial coronary artery shows a delayed recovery following vasoconstrictor stimuli, due to appropriate smooth muscle reactivity and impairment of endothelial-dependent vasodilator capacity.