Kudlacz E M, Logan D E, Shatzer S A, Farrell A M, Baugh L E
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
Eur J Pharmacol. 1993 Sep 7;241(1):17-25. doi: 10.1016/0014-2999(93)90927-a.
Tachykinins, in particular neurokinin A and substance P, produce a number of airway effects which may contribute to respiratory diseases such as asthma. We examined the ability of aerosolized substance P, neurokinin A or capsaicin to produce respiratory alterations in conscious guinea pigs using modified whole body plethysmography. Substance P-mediated dyspnea and significant respiratory events were inhibited by the NK1 receptor antagonist, CP-96,345. Neurokinin A-mediated respiratory effects were ablated by the NK2 receptor antagonists: MEN 10207, MDL 29,913 and SR 48,968, the latter being the most potent. The peptide-based antagonist, MEN 10207, produced respiratory effects itself suggesting partial agonist activity. The cyclic hexapeptide, MDL 29,913, relaxed airway smooth muscle via mechanisms other than tachykinin antagonism. NK2 but not NK1 receptor antagonists were able to delay the onset of capsaicin-induced dyspnea, although alone they did not usually (in approximately 10% of the animals) eliminate the response. However, when NK2 receptor antagonists were combined with CP-96,345, the incidence of dyspnea induced by capsaicin decreased significantly (40%) suggesting that both tachykinins contribute to dyspnea in this system.
速激肽，尤其是神经激肽A和P物质，会产生多种气道效应，这些效应可能会导致哮喘等呼吸系统疾病。我们使用改良的全身体积描记法，研究了雾化的P物质、神经激肽A或辣椒素在清醒豚鼠中引起呼吸改变的能力。NK1受体拮抗剂CP-96,345可抑制P物质介导的呼吸困难和显著的呼吸事件。神经激肽A介导的呼吸效应可被NK2受体拮抗剂消除：MEN 10207、MDL 29,913和SR 48,968，其中SR 48,968最有效。基于肽的拮抗剂MEN 10207自身会产生呼吸效应，提示其具有部分激动剂活性。环状六肽MDL 29,913通过速激肽拮抗作用以外的机制舒张气道平滑肌。NK2而非NK1受体拮抗剂能够延迟辣椒素诱导的呼吸困难的发作，尽管单独使用时它们通常（约10%的动物）不能消除该反应。然而，当NK2受体拮抗剂与CP-96,345联合使用时，辣椒素诱导的呼吸困难的发生率显著降低（40%），这表明两种速激肽都对该系统中的呼吸困难有影响。
