Background. Clinical and morphological studies clearly indicate that most human coronary artery stenoses are capable of vasomotion. Variable ischemic thresholds, ischemia unrelated to work load, and variant angina further show the presence and importance of vasoconstriction in coronary artery stenosis. Despite the importance of vasoconstriction, the effect of intraluminal pressure on the hemodynamic response to vasoconstrictors has not yet been examined. Intraluminal pressure is a primary determinant of vessel size and the force opposing vasoconstriction. Accordingly, we examined the effects of intraluminal pressure on the hemodynamic response to norepinephrine (NE)-induced vasoconstriction. Methods and Results. In canine carotid arteries perfused with physiological salt solution, pressures at the proximal and distal ends of the artery, as well as flow, were continuously recorded. We altered intraluminal pressure using three diverse interventions: changes in perfusion pressure, decreasing distal resistance, and collaterals. In normal, nonstenotic arteries, NE decreased the external vessel diameter but did not reduce flow. Perfusion pressure changes did not affect the ED50 of the NE-diameter relation. After an intraluminal stenosis was created, NE-induced constriction decreased flow. The threshold concentration of NE needed to decrease flow decreased as the perfusion pressure decreased (38.5±17.9, 2.3±1.3, and 0.12±0.1 x 10-7 mol/l for 125, 100, and 75 mm Hg of perfusion pressure, respectively; p<0.05). Lowering distal resistance decreased stenotic pressure and decreased the threshold NE concentration from 5.4±1.9 to 0.34±0.2x10-7 mol/l (p<0.05), and increasing stenotic pressure with collaterals increased the threshold NE concentration from 2.6±1.4 to 7.5±4.6x10-7 mol/l (p<0.05). Conclusions. In stenotic arteries, interventions that lowered the intraluminal pressure decreased the threshold NE concentration needed to decrease flow, and interventions that raised the intraluminal pressure increased the threshold NE concentration. This pressure-dependent constrictor sensitivity affects the vasomotor tone and is important in pathophysiology of ischemia occurring with hypotension (low perfusion pressure) or mild increase in myocardial oxygen demand (low distal arteriolar resistance). The results also suggest that collaterals, by maintaining stenotic pressure, could decrease the constrictor sensitivity and prevent ischemia.