Tachykinins Mediate the Acute Increase in Airway Responsiveness Caused by Toluene Diisocyanate in Guinea Pigs

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Abstract
Exposing guinea pigs to toluene diisocyanate (TDI) causes an acute increase in airway responsiveness to inhaled acetylcholine. The mechanism of this increase in airway responsiveness is unknown. Capsaicin-sensitive afferent nerves and the tachykinins they release upon activation are important in controlling bronchomotor tone in guinea pigs. To determine whether tachykinins are important in TDI-induced airway hyperresponsiveness, we studied the effects of tachykinin depletion, using capsaicin, and competitive tachykinin antagonism, using (D-Arg1, D-Pro2, D-Trp7.8, Leu11) substance P, on TDI-induced airways hyperresponsiveness. In 9 of 9 untreated animals, TDI exposure caused a large and significant increase in airway responsiveness to acetylcholine. The mean concentration of acetylcholine required to decrease specific airway conductance by 50% below baseline (the PD50) was 1.51% before TDI exposure and 0.17% after TDI exposure (p < 0.0005). Capsaicin treatment had no effect on the PD50 but prevented the TDI-induced increase in airways responsiveness in 10 of 12 animals. (The PD50 was 1.03% bfore TDI and 1.27% after TDI exposure.) Treatment with the tachykinin antagonist (D-Arg1, D-Pro2, D-Trp7.9, Leu11) substance P also abolished the TDI-induced increase in airways responsiveness in all 5 animals treated. Although TDI exposure also causes airways edema, the effect of capsaicin treatment on TDI-induced airway hyperresponsiveness did not result from prevention of airway edema. TDI exposure caused a marked increase in tracheal extravasation of intravenously administered Evans blue dye that was not prevented by capsaicin treatment. Untreated animals exposed to TDI had 116 .+-. 13 .mu.g (mean .+-. SEM) Evans blue per g of tracheal tissue, whereas capsaicin-treated animals exposed to TDI had 139 .+-. 15 .mu.g/g). The results of this study suggest that tachykinins are important in TDI-induced airways hyperresponsiveness and that this effect is not due to the known effect of tachykinins on airways vascular permeability.