This study examined the effects of nitroglycerin and nifedipine on the transmural distribution of myocardial blood flow when ischemia-induced vasodilation of the distal coronary vasculature caused a proximal coronary stenosis to become flow-limiting. Studies were performed in chronically instrumented awake dogs with electromagnetic flowmeter probes and hydraulic occluders on the left circumflex coronary artery. Myocardial blood flow was estimated with 15μ radioactive micropheres. During control conditions, subendocardial (endo) flow significantly exceeded subepicardial (epi) flow (endo:epi = 1.33 ± 0.12). Following a 10-second coronary occlusion, reactive hyperemia occurred with excess arterial inflow resulting in 330 ± 37% blood flow debt repayment. This response was not altered by nitroglycerin (0.015 mg/kg, iv), but was decreased by nifedipine (0.01 mg/kg, iv) to 175 ± 38%, indicating depression of the coronary vasodilator response to a brief ischemic stimulus. When, following a 10-second occlusion, arterial inflow was limited to the preocclusion rate by a proximal stenosis, subepicardial flow increased at the expense of hypoperfusion of the subendocardium (endo/epi decreased to 0.50 ± 0.04; P < 0.01), and the continuing subendocardial ischemia resulted in augmentation of the subsequent reactive hyperemia (debt repayment = 556 ± 5%; P < 0.01). Both nitroglycerin and nifedipine abolished the augmentation of the reactive hyperemic response which occurred when a total occlusion was followed by an interval of coronary stenosis. This effect was associated with enhanced subendocardial blood flow during the interval of restricted inflow, suggesting that both of these agents alleviate the subendocardial hypoperfusion and ischemia which occur in the presence of a proximal flow-limiting coronary stenosis.