Tachykinin-mediated respiratory effects in conscious guinea pigs: modulation by NK1 and NK2 receptor antagonists.
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.
Kudlacz
E M
EM
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
Logan
D E
DE
Shatzer
S A
SA
Farrell
A M
AM
Baugh
L E
LE
D000336:Aerosols; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D015288:Neurokinin A / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D012119:Respiration / Q000187:drug effects*; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000336:Aerosols; D001713:Biphenyl Compounds; D006993:Hypnotics and Sedatives; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; D013373:Substance P; D015288:Neurokinin A; D002211:Capsaicin; C066892:CP 96345