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.
NK-1 RECEPTORS AND VASCULAR-PERMEABILITY IN RAT AIRWAYS
ABELLI, Luigi;
1991
Abstract
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.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
