neurokinin-a and Hyperventilation

Sch 37224 is an experimental antiallergy compound that inhibits hyperventilation-induced bronchoconstriction (HIB) in guinea pigs and cold air bronchospasm in human asthmatics. HIB in guinea pigs may involve the release of tachykinins such as neurokinin A (NKA) and substance P (SP), and the action of Sch 37224 in this model may relate to inhibition of these neuropeptides. We studied the effect of Sch 37224 on the neuropeptide component of HIB that was enhanced in guinea pigs treated with the neutral endopeptidase inhibitors, thiorphan and phosphoramidon. Pulmonary resistance (RL) and dynamic lung compliance (CDyn) were measured in anesthetized, mechanically ventilated guinea pigs. RL and CDyn were measured at baseline (1 ml/100 g tidal volume and 50 breaths/min) and after a 10-min period of hyperventilation (1 ml/100 g, 150 breaths/min). Hyperventilation produced modest changes in RL (+41 +/- 12%) and CDyn (-12 +/- 3%) which were markedly enhanced by treatment with 3 mg/kg of either thiorphan or phosphoramidon (RL + 269 +/- 43% for thiorphan, + 292 +/- 63% for phosphoramidon and CDyn -65 +/- 3% for thiorphan, -51 +/- 13% for phosphoramidon). In the presence of thiorphan or phosphoramidon, the bronchospasm to hyperventilation was significantly reduced (> 70%) with 5 mg/kg, p.o., of Sch 37224. In other studies, the peptidergic (conducted in the presence of ipratropium bromide and phosphoramidon) bronchoconstrictor response to intravenous nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p.o.). However, Sch 37224 (5 mg/kg, p.o.) had no effect on the bronchoconstrictor response to intravenous NKA. These results indicate that Sch 37224 inhibits the neuropeptide component of HIB and nicotine in guinea pigs and this effect appears to be mediated by the inhibition of the release of tachykinins from airway C fibers.

Topics: Animals; Bronchoconstriction; Bronchoconstrictor Agents; Glycopeptides; Guinea Pigs; Histamine H1 Antagonists; Hyperventilation; Male; Metalloendopeptidases; Naphthyridines; Neurokinin A; Nicotine; Protease Inhibitors; Thiorphan

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.

Topics: Animals; Bronchoconstriction; Capsaicin; Citric Acid; Guinea Pigs; Hyperventilation; Male; Neurokinin A; Oligopeptides; Receptors, Tachykinin; Respiratory Hypersensitivity; Tachykinins