title: NK(2)-receptor mediated contraction in monkey, guinea-pig and human airway smooth muscle.
abstract: 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.
authors.affiliation: Allergy Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Rizzo
authors.forename: A F
authors.initials: AF
authors.lastname: Valentine
authors.forename: R W
authors.initials: RW
authors.lastname: Egan
authors.forename: W
authors.initials: W
authors.lastname: Kreutner
authors.forename: J A
authors.initials: JA
authors.lastname: Hey
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000737:chemistry / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D015925:Cryopreservation; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000737:chemistry / Q000502:physiology*; D015288:Neurokinin A / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000502:physiology*; D013045:Species Specificity
chemical_list: D001549:Benzamides; C092990:GR 159897; D007211:Indoles; C405340:MDL 103392; D010880:Piperidines; D011758:Pyrroles; D011759:Pyrrolidines; D018041:Receptors, Neurokinin-2; C073839:SR 48968; D015288:Neurokinin A