Involvement of capsaicin-sensitive nerves in paraquat-induced mortality

Paraquat (PQ), a broad spectrum herbicide, produces severe lung inflammatio n and necrosis resulting in pulmonary fibrosis and respiratory failure. Tac hykinins are peptides released by sensory C fibers and have the ability of influencing respiratory functions and cellular proliferation. To examine wh ether the damage caused by PQ involves tachykinins, rats were depleted in t heir content of tachykinins by systemic treatment with capsaicin prior to P Q exposure. The animal subjected to this treatment showed a 3-fold higher v iability compared to those treated with PQ alone (75 vs 27%). Depletion of reduced glutathione (GSH) is associated with oxidative stress produced by r eactive oxygen intermediates during PQ metabolism. This is considered to be critical in the pathogenesis of lung damage by PQ. PQ treatment induced a significant depletion of GSH during the first days and a similar effect was also observed in the group of capsaicin-pretreated rats. Four weeks after PQ treatment the levels of GSH were similar to controls in rat pretreated o r not with capsaicin plus PQ. This may indicate that the reduced levels of GSH may be associated to the toxicity observed in the acute phase, but not of importance in the final PQ-induced mortality. Neutral endopeptidase (NEP ) is an enzyme considered to be critical in controlling the levels of tachy kinins. Exposure of crude membrane preparations of rat lung to PQ resulted in a dose-dependent inhibition of NEP activity. Since NEP inactivation may occur in lung following a PQ exposure in vivo, the results indicate that du ring PQ intoxication a more sustained activity of tachykinins may be presen t, producing effects such as cell proliferation, fluid extravasation and br onchoconstriction. In conclusion, this finding supports the hypothesis that neuropeptides released from capsaicin-sensitive nerves could be involved i n the modulation of PQ-induced lung damage. (C) 1998 Elsevier Science Irela nd Ltd. All rights reserved.