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 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, vasodilation and plasma extravasation, as well as the chemoattraction and stimulation of various cells presumed to be involved in asthmatic airway inflammation. NK2 receptors and, to a lesser extent, NK1 receptors have been shown to be involved in bronchoconstriction, whereas NK1 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 NK1 and NK2 receptor antagonist, and CP99994, a nonpeptide NK1 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.
Joos
G F
GF
Department of Respiratory Diseases, University Hospital Ghent, Belgium.
Kips
J C
JC
Peleman
R A
RA
Pauwels
R A
RA
D000818:Animals; D016084:Bronchoconstriction / Q000502:physiology; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D015288:Neurokinin A / Q000502:physiology; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012143:Respiratory Physiological Phenomena; D012137:Respiratory System / Q000187:drug effects; D013373:Substance P / Q000502:physiology; D015320:Tachykinins / Q000494:pharmacology / Q000502:physiology*
D007211:Indoles; D054833:Isoindoles; D018039:Receptors, Tachykinin; D015320:Tachykinins; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D015288:Neurokinin A