The purpose of this study was to test the hypothesis that blood flow, by its effect on blood volume, influences airflow resistance in peripheral airways. In conscious ewes, forced sinusoidal flow oscillations (5 Hz) were applied through a balloon-tipped, dual-channel fiberoptic bronchoscope placed in a segmental bronchus, and peripheral airflow resistance (Rp) was determined from flow and bronchial pressure. Drugs with predominant vascular or airway smooth muscle effects were administered locally through the bronchoscope. Nitroglycerin (NTG) produced a dose-dependent increase in mean Rp (+288% at 1,000 micrograms), which was blocked by methylene blue (p less than 0.05) and not reversed by atropine. Carbachol (CARB) also increased mean Rp in a dose-dependent manner (+605% at 400 micrograms); this effect was not blocked by methylene blue, but it was reversed by atropine (p less than 0.05). The increase in mean Rp after a single dose of NTG (250 micrograms) was sustained for at least 20 min and transiently reversed by vasopressin (0.2 units, p less than 0.05) but not by isoproterenol (100 micrograms). Conversely, the sustained increase in Rp after a single dose of CARB (50 micrograms) was transiently reversed by isoproterenol (p less than 0.05) but not by vasopressin. We conclude that NTG increased Rp by vasodilation and CARB by bronchoconstriction. This supports the hypothesis that vasodilation limits airflow in the lung periphery, presumably because of vascular congestion.