SUBSTANCE-P-INDUCED HISTAMINE-RELEASE IN TRACHEALLY PERFUSED GUINEA-PIG LUNGS

The capacity of substance P (SP) and endogenously released tachykinins to liberate histamine was examined in isolated tracheally perfused gu inea pig lungs. Increasing doses of tracheally injected SP were associ ated with the recovery of increasing amounts of histamine from lung ef fluent. The mechanism of SP-induced histamine liberation was explored in studies with neurokinin-(NK) receptor agonists and antagonists. Tra cheal injection of either the NK1 agonist [Sar(9),Met(O-2)(11)]SP or t he NK2 agonist [beta-Ala(8)]-neurokinin A-(4-10) was associated with a significant increase in histamine recovery from lung effluent. In add ition, both the NK1 antagonist CP-99994 and the NK2 antagonist SR-4896 8 significantly inhibited SP-induced histamine release. These findings support the hypothesis that SP can liberate histamine from guinea pig lungs by a mechanism that depends predominantly on NK1- and NK2-recep tor activation. The Liberation of endogenous tachykinins by acute trac heal injection of capsaicin was also associated with augmented histami ne recovery, which was inhibited by combined NK1- and NK2-receptor blo ckade. Tracheal injection of SP was associated with an increase in the percentage of airway mast cells exhibiting histological evidence of d egranulation. This study demonstrates that exogenous SP, as well as en dogenous tachykinins released from capsaicin-sensitive neurons, can li berate histamine, most likely from airway mast cells, by a mechanism t hat depends predominantly on the activation of NK1 and NK2 receptors.