Shear stress-dependent nitric oxide (NO) formation prevents immoderate vascular constriction. We examined whether shear stress-dependent NO formation limits exercise-induced coronary artery constriction after -adrenergic receptor blockade in dogs. Control exercise led to increases (P < 0.01) in coronary blood flow (CBF) by 38 ± 5 ml/min from 41 ± 5 ml/min and in the external diameter of epicardial coronary arteries (CD) by 0.24 ± 0.03 mm from 3.33 ± 0.20 mm. CD and shear stress were linearly related. After propranolol, CD fell (P < 0.01) during exercise (0.08 ± 0.03 from 3.23 ± 0.19 mm), and the slope of the relationship between CD and shear stress was reduced (P < 0.01). This slope was not further altered by the additional blockade of NO formation. In propranolol-treated resting dogs, flow-dependent effects of intracoronary adenosine to mimic exercise-induced increases in shear stress (after propranolol) led to increases (P < 0.01) in CD (0.09 ± 0.02 from 3.68 ± 0.27 mm). Thus both shear stress-dependent NO formation and -adrenergic receptor activation are required to cause CD dilation during exercise. Suppression of -adrenergic receptor activation leads to impaired shear stress-dependent NO formation and allows -adrenergic constriction to become dominant.