TACHYKININ ANTAGONISTS AND THE AIRWAYS

There is now convincing evidence for the presence of substance P (SP) and neurokinin A (NKA) in human airway nerves. Studies on autopsy tiss ue, on bronchoalveolar lavage fluid and on sputum suggest that SP may be present in increased amounts in the asthmatic airway. Substance P a nd NKA are potent bronchoconstrictors of human airways, asthmatics bei ng more sensitive than normal persons. The major enzyme responsible fo r the degradation of the tachykinins, the neutral endopeptidase, is pr esent in the airways and is involved in the breakdown of exogenously a dministered SP and NKA, both in normal and asthmatic persons. Other, l ess well documented airway effects of SP and NKA include mucus secreti on, vasodilatation and plasma extravasation, as well as the chemoattra ction and stimulation of various cells presumed to be involved in asth matic airway inflammation. NK2 receptors and, to a lesser extent, NK1 receptors have been shown to be involved in bronchoconstriction, where as NK, receptors were found to be involved in mucus secretion, microva scular leakage and vasodilatation, and in most of the effects on infla mmatory cells. The first clinical trial with FK224, a peptide NK1 and NK2 receptor antagonist, and CP99994, a nonpeptide NK1 receptor antago nist, are negative. However, FK224 failed to block the bronchoconstric tor effect of NKA in asthmatics and the dose of CP99994, needed to ant agonize tachykinin effects in man, remains to be determined.