Antagonism by NKP608 of substance P-induced plasma protein exudation in a novel preparation of perfused trachea in rats and guinea-pigs in vivo.
OBJECTIVE
To examine whether NKP608, a novel 1-benzoyl-2-benzyl-4-aminopiperidine NK1 receptor antagonist, inhibits substance P (SP)-induced airway plasma protein exudation in vivo.


METHODS
Anaesthetised English shorthair guinea-pigs and Wistar rats.


METHODS
Tachykinin peptides were applied topically onto the trachea and antagonists administered intravenously.


METHODS
Tracheal segments isolated in situ were perfused with saline and plasma-derived protein assayed in the perfusate.


RESULTS
SP (1 microM) caused plasma protein exudation, which was abolished by an NK1 antagonist (RP 67580,1.75 micromol/kg) but unaffected by an NK2 antagonist (SR 48968, 1.75 micromol/ kg) indicating the response is NK1-receptor-mediated. This was confirmed with a response to an NK1 agonist ([Sar9, Met(O2)11]-SP, 1 microM) but none to an NK2 agonist ([betaAla8]-neurokinin A(4-10), 1 microM). NKP608 inhibited SP responses with estimated ID50 values (micromol/kg) of 0.0044 (guinea-pigs) and 0.19 (rats).


CONCLUSIONS
NKP608 is an antagonist in vivo of NK1 receptor-induced tracheal plasma protein exudation and is more potent in guinea-pigs than rats.
Coulson
F R
FR
Department of Physiology and Pharmacology, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Bigg
C S
CS
O'Donnell
S R
SR
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005122:Exudates and Transudates / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013618:Tachyphylaxis; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
D001798:Blood Proteins; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides; D010880:Piperidines; D011804:Quinolines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C414491:quinoline-4-carboxylic acid (1-(3,5-bis-trifluoromethylbenzoyl)-2-(4-chlorobenzyl)piperidin-4-yl)amide; D013373:Substance P