TACHYKININ-MEDIATED RESPIRATORY EFFECTS IN CONSCIOUS GUINEA-PIGS - MODULATION BY NK(1) AND NK(2) RECEPTOR ANTAGONISTS

Tachykinins, in particular neurokinin A and substance P, produce a num ber of airway effects which may contribute to respiratory diseases suc h as asthma. We examined the ability of aerosolized substance P, neuro kinin A or capsaicin to produce respiratory alterations in conscious g uinea pigs using modified whole body plethysmography. Substance P-medi ated 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 2 9,913 and SR 48,968, the latter being the most potent. The peptide-bas ed antagonist, MEN 10207, produced respiratory effects itself suggesti ng partial agonist activity. The cyclic hexapeptide, MDL 29,913, relax ed airway smooth muscle via mechanisms other than tachykinin antagonis m. NK2 but not NK1 receptor antagonists were able to delay the onset o f capsaicin-induced dyspnea, although alone they did not usually (in a pproximately 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%) suggesti ng that both tachykinins contribute to dyspnea in this system.