The present study was undertaken to evaluate the role of sympathetic nerves in increasing lung vascular permeability. An isolated rat sympathetic nerve-lung preparation was used. Three minutes after an increase in lung weight was induced by elevating the intravascular pressure, stimulation of sympathetic nerves was performed in the presence of papaverine, which further increased the lung weight in a graded manner. After the nerve stimulation, deposits of carbon were observed in alveolar macrophages and perivascular walls, indicating an increase in vascular permeability. The response of lung weight to the sympathetic nerve stimulation was altered, depending on the magnitude of intravascular pressure change as well as on the voltage and frequency of electrical stimulation. Furthermore, these responses were prevented by tetrodotoxin. Calculation of the relationship between the maximal slope of the graded lung weight gain and the slope obtained just before the nerve stimulation gave a slope ratio at a frequency of 30 cps in normal rats of 4.47 +/- 0.21. Treatment with phentolamine diminished the value to 1.93 +/- 0.15, and with reserpine, to 1.43 +/- 0.14. In reserpinized rats, the slope ratio was restored by an administration of norepinephrine to 2.11 +/- 0.05 at 30 cps, being further increased by propranolol and blocked partially by phentolamine. The capillary filtration coefficient was not affected by either of the agents. In capsaicin-treated rats, sympathetic nerve stimulation did not cause any response in terms of lung weight (slope ratio = 1.0). These results indicate that unknown neurotransmitters released from the capsaicin-sensitive nerves may participate in increasing the lung vascular permeability, and that norepinephrine may play a role in regulation via alpha- and beta-adrenoceptors.