title: Tachykinins mediate the acute increase in airway responsiveness caused by toluene diisocyanate in guinea pigs.
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-Trp7.9, Leu11) substance P, on TDI-induced airway 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 less than 0.0005). Capsaicin treatment had no effect on the PD50 but prevented the TDI-induced increase in airway responsiveness in 10 of 12 animals. (The PD50 was 1.03% before 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 airway responsiveness in all 5 animals treated. Although TDI exposure also causes airway 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.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology / Q000627:therapeutic use; D003485:Cyanates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005070:Evans Blue / Q000378:metabolism; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D018039:Receptors, Tachykinin; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D015320:Tachykinins; D014051:Toluene 2,4-Diisocyanate / Q000494:pharmacology*; D014132:Trachea / Q000378:metabolism
chemical_list: D003485:Cyanates; D009479:Neuropeptides; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; D014051:Toluene 2,4-Diisocyanate; D013373:Substance P; D005070:Evans Blue; C038073:substance P, Arg(1)-Pro(2)-Trp(7),(9)-LeuNH(2)(11)-; D000109:Acetylcholine; D002211:Capsaicin