The effects of vagal stimulation on pulmonary vascular permeability were studied in guinea pigs in vivo using 125I-labeled albumin as a marker of plasma extravasation. Bilateral vagus nerve stimulation (NS) significantly increased the plasma leakage index in both parenchyma and tracheobronchial tissues. The NS-induced plasma leakage in the parenchyma was unaffected by the alpha-adrenoceptor antagonist phentolamine, the muscarinic receptor antagonist atropine, the ganglionic blocker hexamethonium, or pretreatment with 6-hydroxydopamine or capsaicin, but it was significantly potentiated by the beta-adrenoceptor antagonist propranolol. NS-induced tracheobronchial vascular leakage was markedly inhibited by pretreatment with atropine, hexamethonium, or capsaicin, although it was unaffected by pretreatment with phentolamine, propranolol, or 6-hydroxydopamine. By itself, NG-nitro L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, had no effect on pulmonary vascular leakage, but it significantly enhanced the NS-induced plasma leakage to parenchyma in a dose-related and L-arginine-reversible manner. Elevation of blood pressure to a similar extent as that induced by L-NAME by a phenylephrine infusion had no significant effect on the increased plasma leakage induced by NS. These results suggest that vagal stimulation increases plasma extravasation in lung parenchyma through the release of unidentified transmitter(s) in a process that is modulated by endogenous NO and catecholamines (via activation of beta-adrenoceptors), and that different mechanisms are involved in the vagally induced plasma extravasation in the pulmonary and tracheobronchial vascular beds.