Short-term continuous nitroglycerin delivery by the intrave- nous or transdermal route for only 2 to 4 hours protects the endothelium from experimental ischemia in healthy volun- teers and reduces ischemia during coronary angioplasty and physical exercise in IHD patients.863 865 Oxygen free radical release seems to be associated with these protective out- comes. Nitroglycerin causes dilation of the artery wall not affected by plaque, but independent of an intact endothelium, leading to reduced resistance across the obstructed lumen.866 Furthermore, nitroglycerin contributes to coronary blood flow redistribution, by augmenting collateral flow and lowering ventricular diastolic pressure, from areas of normal perfusion to ischemic zones.867 Preload is reduced, leading to reduc- tions in myocardial wall tension and myocardial oxygen demand, although this effect is offset by increased heart rate and myocardial contractile state due to reflex sympathetic activity. Nitroglycerin also has demonstrated antithrombotic and antiplatelet effects.868,869 Long-term nitrate therapy, however, could offset the beneficial short-term ischemic preconditioning effects. Long- term nitroglycerin therapy is associated with endothelial dysfunction via accumulation of the same oxygen free radi- cals that seem to be beneficial in short-term administra- tion.870,871 The oxygen free radical accumulation increases arterial sensitivity to vasoconstrictors such as angiotensin II, which can be counteracted by concomitant treatment with an ACE inhibitor or hydralazine.872 875 Importantly, these phys- iological changes are independent of dose or the presence or absence of a nitrate-free interval and can result in a decrease in the anginal threshold during the nitrate-free interval.876 Further research to better understand the balance between the long-term benefits and safety concerns of these compounds is warranted in patients with SIHD. 