Foulon D M, Champion E, Masson P, Rodger I W, Jones T R
Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
Am Rev Respir Dis. 1993 Oct;148(4 Pt 1):915-21. doi: 10.1164/ajrccm/148.4_Pt_1.915.
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), beta Ala8-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 beta Ala8-NKA(4-10) > NKA > Sar9-Met(O2)11Sp > SP >> NKB. The DRC to the selective NK1 agonist Sar9-Met(O2)11SP was shifted to the right 10-fold by the selective NK1 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 NK2 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.(ABSTRACT TRUNCATED AT 250 WORDS)
本研究对麻醉豚鼠中神经激肽受体介导的支气管收缩反应进行了特征描述。因此，我们比较了选择性神经激肽1（NK1）（CP - 99,994）和神经激肽2（NK2）（SR - 48,968）受体拮抗剂对静脉注射P物质（SP）、神经激肽A（NKA）、神经激肽B（NKB）、β丙氨酸8 - NKA（4 - 10）、Sar9 - Met（O2）11SP以及用辣椒素样感觉神经毒素树脂毒素（RTX）、白三烯D4（LTD4）和抗原进行单剂量（静脉）激发所诱导的剂量反应曲线（DRC）的作用。神经激肽诱导支气管收缩的效力顺序为β丙氨酸8 - NKA（4 - 10）> NKA > Sar9 - Met（O2）11Sp > SP >> NKB。选择性NK1激动剂Sar9 - Met（O2）11SP的DRC被选择性NK1拮抗剂CP - 99,994（1毫克/千克，静脉注射）向右移动了10倍，但未被SR - 48,968（3毫克/千克，静脉注射）移动。选择性NK2激动剂β - Ala8 - NKA（4 - 10）的DRC被NK2拮抗剂SR - 48,968（1毫克/千克）向右移动了82倍，但未被CP - 99,994（3毫克/千克，静脉注射）移动。SR - 48,968（1毫克/千克）也阻断了NKA（3倍移动）但未阻断SP。CP - 99,994未能使SP或NKA的DRC产生显著的向右移动。然而，1毫克/千克CP - 99,994和1毫克/千克SR - 48,968的组合使SP（> 5倍）和NKA（> 300倍）的DRC产生了显著移动。NKA和SP诱导的低血压也被该组合阻断。（摘要截短于250字）
