NK(2)-receptor mediated contraction in monkey, guinea-pig and human airway smooth muscle

Neurokinins (NK) are implicated in airway pathology. Selective NK(2)-receptor antagonists may prove therapeutic in airway disease. We studied Neurokinin A (NKA) responses of isolated, cryopreserved cynomolgus monkey, fresh guinea pig, and fresh and cryopreserved human airways. NKA contracted monkey...

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Published in:Neuropeptides (Edinburgh) 1999-02, Vol.33 (1), p.27-34
Main Authors: Rizzo, C A, Valentine, A F, Egan, R W, Kreutner, W, Hey, J A
Format: Article
Language:English
Subjects:
Animals
Benzamides - pharmacology
Bronchi - chemistry
Bronchi - physiology
Bronchoconstriction - drug effects
Bronchoconstriction - physiology
Cryopreservation
Female
Guinea Pigs
Humans
Indoles - pharmacology
Macaca fascicularis
Male
Muscle Contraction - drug effects
Muscle Contraction - physiology
Muscle, Smooth - chemistry
Muscle, Smooth - physiology
Neurokinin A - pharmacology
Piperidines - pharmacology
Pyrroles - pharmacology
Pyrrolidines - pharmacology
Receptors, Neurokinin-2 - physiology
Species Specificity
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Summary:Neurokinins (NK) are implicated in airway pathology. Selective NK(2)-receptor antagonists may prove therapeutic in airway disease. We studied Neurokinin A (NKA) responses of isolated, cryopreserved cynomolgus monkey, fresh guinea pig, and fresh and cryopreserved human airways. NKA contracted monkey trachea (pD(2)= 7.9), guinea-pig bronchus (pD(2)= 8.8) and human bronchus (pD(2)= 7.1). Potency rank order (pK(b)) of NK(2)-antagonists, SR 48968 and GR 159897, and a dual NK(1)/NK(2)-antagonist, MDL 103392, against NKA responses in monkey trachea, guinea pig and human bronchus, respectively, were SR 48968 (9.29 +/- 0.11, 9.15 +/- 0.10 and 9.51 +/- 0.17) > GR 159897 (8.45 +/- 0.26, 8.19 +/- 0.13 and 8.57 +/- 0. 22) > MDL 103392 (6.55 +/- 0.13, 6.97 +/- 0.14 and 7.16 +/- 0.13). CP 99994 (1 microM), a NK(1)-receptor antagonist, was inactive against NKA responses in all three species. The NK(3)-antagonist SR 142801 (1 microM) was inactive against NKA in monkey trachea and guinea-pig bronchus, but demonstrated weak antagonist activity (pK(b)= 6.97 +/- 0.03) in human bronchus. These findings demonstrate that NK(2)-receptors mediate tracheal smooth muscle contraction to NKA in cynomolgus monkey and that the pharmacological responsiveness of airway NK(2)-receptors in the three species studied is similar. Furthermore, our results suggest that cryopreservation may extend the viability of human and non-human primate airway tissue for studies of neurokinin receptor pharmacology. Studies are needed to further determine the similarity in neurokinin pharmacology between fresh and cryopreserved airway tissue.
ISSN:0143-4179