[Effect of a novel tachykinin NK-2-receptor antagonist, TAC-363, on bronchoconstriction and airway hyperresponsiveness in guinea pigs].
We examined the effect of a novel tachykinin NK-2-receptor antagonist, N alpha-(tert-Butylcarbamoyl)-L-glutaminyl-L-tryptophyl-alpha-aza- phenylalanine 2-benzyloxyethylamide (TAC-363), on hyperventilation- and citric acid-induced bronchoconstriction and neurokinin A (NKA)-, capsaicin- and antigen-induced airway hyperresponsiveness in guinea pigs. The i.v. administration of TAC-363 at doses of 0.01-1 mg/kg inhibited hyperventilation- and citric acid-induced bronchoconstriction in a dose-dependent manner, while FK-888, a tachykinin NK-1-receptor antagonist, did not inhibit hyperventilation-induced bronchoconstriction. NKA-induced airway hyperresponsiveness to acetylcholine was attenuated by i.v. injection of TAC-363, but not by the thromboxane A2 synthetase inhibitor ozagrel and the mast cell stabilizer DSCG. Furthermore, TAC-363 prevented the occurrence of capsaicin- and antigen-induced airway hyperresponsiveness to acetylcholine, while FK-888 did not prevent occurrence of capsaicin-induced airway hyperresponsiveness. In summary, TAC-363 inhibits bronchoconstriction and airway hyperresponsiveness induced by various stimuli. These results suggest that NKA mediates bronchoconstriction and airway hyperresponsiveness. Thus, TAC-363 is expected to be useful in the treatment of airway diseases such as asthma.
Higashide
Y
Y
Pharmaceuticals Research Laboratories, Fujirebio, Inc., Tokyo, Japan.
Yatabe
Y
Y
Arai
Y
Y
Shibata
M
M
Yamaura
T
T
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D019343:Citric Acid / Q000494:pharmacology; D006168:Guinea Pigs; D006985:Hyperventilation / Q000503:physiopathology; D008297:Male; D015288:Neurokinin A / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D012130:Respiratory Hypersensitivity / Q000517:prevention & control*; D015320:Tachykinins / Q000037:antagonists & inhibitors*
D009842:Oligopeptides; D018039:Receptors, Tachykinin; C103891:TAC 363; D015320:Tachykinins; D019343:Citric Acid; D015288:Neurokinin A; D002211:Capsaicin