NK‐1 Receptors and VascularPermeability in Rat Airways

This is the authors' abstract. We don't add key points for this paper.

The ability of synthetic tachykinin analogues to increase vascular permeability in the tracheobronchial region of urethane (1.2 g/kg sc)-anesthetized male Wistar rats was investigated in order to characterize the tachykinin receptor subtype(s) involved. Plasma protein extravasation was evaluated by means of the Evan's Blue (20 mg/kg iv) leakage technique at 5 minutes after intravenous administration of the test substances. The NK-1 selective agonists, namely, [beta-Ala4,Sar9]SP(4-11) sulfone and [pGlu6,Pro9]SP(6-11), were dose-dependently effective (0.037-3.7 nmol/kg), whereas the NK-2 ([beta-Ala8]NKA(4-10) and [Nle10]NKA(4-10)) and NK-3 ([MePhe7]NKB) selective agonists were inactive. These findings provide evidence that the response of the airways to intravenous tachykinins is exclusively mediated by the NK-1 receptor subtype. The response to the NK-1 agonist, [bata-Ala4,Sar9]SP(4-11) sulfone, a compound devoid of mast cell-degranulating activity, was not modified by pretreatment with BW 755C (188 pmol/kg iv, 5 min before), whereas the effect of an equimolar dose (3.7 nmolkg iv) of substance P (SP) was dose-dependently inhibited (up to 50%) by the dual cyclooxygenase and lipoxygenase inhibitor (56-1 88 pmol/kg). The involvement of LTC, and LTD, in the response to SP was ruled out by the ineffectiveness of the leukotriene antagonist, FPL 55712 (8.9 pmol/kg iv, 2 min before), and of the inhibitor of leukotriene synthesis, U-60257B (43.2 pmol/kg iv, 8 min before). Conversely, the response to SP of rats pretreated subcutaneously with the mast cell-degranulating compound 48/80 (5 mg/kg daily for 3 days) was reduced by 30% (n = 12 rats per group, P<0.05). In conclusion, the effect of SP on vascular permeability appears to be mediated by a receptor-coupled action on NK-1 sites, for which SP has preferential affinity, and through the release of endogenous prostanoids. The latter mechanism appears to be activated by the N-terminal basic residues of SP, which are responsible for the mast cell-degranulating activity of the neuropeptide.