CHARACTERIZATION OF NEUROGENIC INFLAMMATION IN THE AIRWAYS OF 2 HIGHLY INBRED RAT STRAINS

Tachykinins released from sensory airway nerves have been shown to inc rease vascular permeability and plasma-protein extravasation (PPE) in rodent airways. We previously demonstrated that in Fisher (F344) rats, tachykinins cause bronchoconstriction mainly by indirect mechanisms i nvolving the activation of NK1 receptor and mast cells, whereas in the less responsive BDE rats tachykinins have a direct NK2 receptor-media ted effect on bronchial smooth muscle. Using Evans blue dye as an intr avascular marker, we demonstrated that F344 rats are hyperresponsive f or the PPE induced by substance P (SP) and capsaicin. The NK1 receptor antagonist RP 67,580 reduced the neurogenic PPE in both strains, wher eas the NK2 receptor antagonist SR 48,968 had no effect, indicating th at only NK1 receptors are involved in the PPE. Pretreatment with the 5 -HT antagonist methysergide decreased the neurogenic PPE in F344 rats but not in BDE rats. In F344 rats depleted of mast-cell mediators with compound 48/80, the SP-induced PPE was significantly reduced. Pretrea tment with the H-1 antagonist mepyramine and the H-2 antagonist cimeti dine caused a similar reduction in SP-induced PPE in main bronchi of b oth strains. Pretreatment with atropine, indomethacin, or the leukotri ene antagonist ICI 198,615 did not affect the SP-induced PPE. In concl usion, neurogenic PPE in rat airways involves the activation of NK1 re ceptors. In F344 but not in BDE rats, an additional indirect mechanism involving 5-HT release and mast-cell activation participates in the n eurogenic PPE.