This study demonstrates that flow velocity modulates coronary venular permeability to albumin. Apparent permeability coefficients of albumin (Pa) were measured in isolated cannulated coronary venules ranging from 30 to 70 microns in diameter. Hydrostatic and oncotic pressures were controlled while the intraluminal flow velocity was varied. Pa at an intraluminal hydrostatic pressure of 12 cmH2O and a flow velocity of 7 mm/s was 4.01 +/- 0.53 x 10(-6) cm/s. Increasing flow velocity to 10 and 13 mm/s augmented the permeability by 33 +/- 14 and 48 +/- 14%, respectively. The nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) (10(-5) M), decreased baseline Pa and abolished the flow-induced permeability changes. Administration of L-arginine (3 x 10(-3) M), a physiological precursor of nitric oxide which reverses the effect of L-NMMA, restored the relationship between flow and permeability. From these results we conclude that 1) flow velocity should be considered as a physical force that potentially modulates permeability of venular exchange vessels in the heart and 2) flow modulates coronary venular permeability via the production of nitric oxide.