NK(1) AND NK(2) RECEPTORS MEDIATE TACHYKININ AND RESINIFERATOXIN-INDUCED BRONCHOSPASM IN GUINEA-PIGS

The present study characterized neurokinin receptor-mediated bronchoconstrictor responses in anesthetized guinea pigs. Thus, we have compared the actions of the selective neurokinin 1 (NK1) (CP-99,994) and neurokinin 2 (NK2) (SR-48,968) receptor antagonists against dose-response curves (DRC) induced by intravenously administered substance P (SP), neurokinin A (NKA), neurokinin B (NKB), betaAla8-NKA (4-10),Sar9-Met(O2)11SP, and single dose (intravenous) challenge with resiniferatoxin (RTX), a capsaicin-like sensory neurotoxin, leukotriene D4 (LTD4) and antigen. The rank order of potency of the neurokinins for inducing bronchoconstriction was betaAla8-NKA(4-10) > NKA > Sar9-Met(O2)11 SP > SP >> NKB. The DRC to the selective NK1 agonist Sar9-Met(O2)11SP was shifted to the right 10-fold by the selective NK2 antagonist, CP-99,994 (1 mg/kg, intravenously), but was not shifted by SR-48,968 (3 mg/kg, intravenously). The DRC to the selective NK, agonist beta-Ala8-NKA(4-10) was shifted to the right 82-fold by the NK2 antagonist, SR-48,968 (1 mg/kg), but was not shifted by CP-99,994 (3 mg/kg, intravenously). SR-48,968 (1 mg/kg) also blocked NKA (3-fold shift) but did not block SP. CP-99,994 failed to produce a significant rightward shift of the DRC to either SP or NKA. However, the combination of 1 mg/kg CP-99,994 and 1 mg/kg SR-48,968 produced significant shifts of the DRCs to SP (> 5-fold) and NKA (> 300-fold). Hypotension induced by NKA and SP was also blocked by this combination. Neither airway nor vascular responses to SP and NKA were blocked by atropine; mepyramine; methysergide; indomethacin; the LTD, receptor antagonist, MK-679; or the leukotriene biosynthesis inhibitor, MK-0591. Bronchoconstriction to intravenously administered RTX (5 mug/kg) was partly inhibited by SR-48,968 (3 mg/kg) but was completely inhibited by a combination of SR-48,968 (0.3 mg/kg) and CP-99,994 (0.3 mg/kg). Bronchoconstriction to LTD4 and antigen was not inhibited by the combination of NK, and NK, antagonists. These results indicate that NKA, SP, and RTX produce bronchoconstriction in the guinea pig through NK, and NK, receptor stimulation. Moreover, part of the hypotension response to intravenous RTX and SP and part of the BC response to SP was resistant to blockade by NK2 and NK, receptor antagonists.