Release of Substance P from Guinea Pig Trachea Leukotriene D₄

Abstract

Coordinated studies of leukotriene D4 (LTD ₄)-mediated contractile responses and LTD4-evoked release of the tachykinin substance P (SP) in both intact and epithelium abraded guinea pig tracheal smooth muscle preparations were performed. A partial contribution by axon reflex mechanisms to the magnitude of LTD₄-induced tracheal contractions was suggested by a maximum inhibition of 21% and 28% by 5 × 10≈⁶M tetrodotoxin (TTX) in abraded and intact preparations, respectively. SP-induced contractions were antagonized by the SP analog [DPro⁴DTrp^7,9]-SP 4-11 in both types of preparation. The SP analog produced 58% and 72% inhibition of contractile responses to 10^-8M LTD₄ in abraded and intact preparations, respectively. Direct measurement of SP release by radioimmunoassay of the bathing medium showed TTX-sensitive LTD₄-evoked release of SP Inhibition by 5 × 10^-6M TTX of LTD₄-evoked SP release was 77%. The SP antagonist produced greater inhibition of LTD₄-evoked contractions (58% in abraded, and 72% in intact preparations) than maximum TTX inhibition of LTD₄-evoked contractions (21% in abraded, and 28% in intact). However, LTD₄ (10′⁸M)-evoked SP release was at least 77% blocked by maximum doses of TTX. We therefore suggest that an additional agent, released by TTX-insensitive mechanisms, but whose contractile effects are also antagonized by [DPro⁴DTrp^7,9]-SP 4-11, may participate in the LTD₄ response.