Mechanism of tachyphylaxis associated with neurogenic plasma extravasation in the rat trachea

Electrical stimulation of the vagus nerve of rats is known to produce plasma extravasation in the trachea, presumably by releasing substance P or other tachykinins from sensory nerves. We sought to determine whether the tachyphylaxis that develops after prolonged vagal stimulation results from an inability of sensory nerves to release tachykinins or from an inability of tracheal blood vessels to respond to tachykinins. To induce tachyphylaxis, we electrically stimulated the right vagus nerve of Long-Evans rats for 5 min (5 V, 1 ms, 20 Hz). Then, 10 min later, we gave intravenous injections of capsaicin (0.3 mumol/kg), histamine (18 mumols/kg), or substance P (2.2 nmol/kg), which produce equivalent amounts of plasma extravasation as assessed by the extravasation of Evans blue dye. We found that vagal stimulation reduced the amount of dye extravasation produced by capsaicin but not the amount produced by either histamine or substance P. We also found that pretreating neonatal rats with capsaicin, which destroys tachykinin-containing sensory nerves, reduced the amount of dye extravasation produced by capsaicin but not the amount produced by either histamine or substance P. This finding suggests that capsaicin produces plasma extravasation in the trachea by releasing tachykinins from sensory nerves, whereas histamine and substance P do so by acting directly on tracheal blood vessels. Taken together, our results indicate that prolonged vagal stimulation reduces the ability of sensory nerves to release tachykinins but that tracheal blood vessels remain fully responsive to both histamine and substance P.