Tachykinin antagonists and the airways
Joos, G.F.; Kips, J.C.; Peleman, R.A.; Pauwels, R.A.
Archives Internationales de Pharmacodynamie et de Therapie 329(1): 205-219
1995
ISSN/ISBN: 0003-9780 PMID: 7543746 Document Number: 448499
There is now convincing evidence for the presence of substance P (SP) and neurokinin A (NKA) in human airway nerves. Studies on autopsy tissue, on bronchoalveolar lavage fluid and on sputum suggest that SP may be present in increased amounts in the asthmatic airway. Substance P and NKA are potent bronchoconstrictors of human airways, asthmatics being more sensitive than normal persons. The major enzyme responsible for the degradation of the tachykinins, the neutral endopeptidase, is present in the airways and is involved in the breakdown of exogenously administered SP and NKA, both in normal and asthmatic persons. Other, less well documented airway effects of SP and NKA include mucus secretion, vasodilatation and plasma extravasation, as well as the chemoattraction and stimulation of various cells presumed to be involved in asthmatic airway inflammation. NK-2 receptors and, to a lesser extent, NK-1 receptors have been shown to be involved in bronchoconstriction, whereas NK-1 receptors were found to be involved in mucus secretion, microvascular leakage and vasodilatation, and in most of the effects on inflammatory cells. The first clinical trial with FK224, a peptide NK-1 and NK-2 receptor antagonist, and CP99994, a nonpeptide NK-1 receptor antagonist, are negative. However, FK224 failed to block the bronchoconstrictor effect of NKA in asthmatics and the dose of CP99994, needed to antagonize tachykinin effects in man, remains to be determined.