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 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. Copyright 1999 Harcourt Brace & Co. Ltd.