FK-224

Tachykinins are thought to mediate hyperpnea-induced bronchoconstriction (HIB).It was reported that tachykinin receptor antagonists, FK888 (a selective neurokinin 1 receptor antagonist) and FK224 (a dual neurokinin 1/neurokinin 2 receptor antagonist) inhibited bronchoconstriction in asthmatics.To determine the role of tachykinin receptor antagonists on HIB, we tested the effect of FK888 and FK224 during dry gas hyperpnea challenge in sensitized guinea pigs.Sensitized guinea pigs, pretreated with FK888 and FK224 i.v., were anesthetized and artificially ventilated with dry gas hyperpnea for 5 min.A control group was also studied.After the challenge, lung resistance was measured for 60 min.Bronchoalveolar lavage fluid was obtained for cell counts.Substance P, neurokinin A, nerve growth factor, prostaglandin E2, thromboxane B2, and 9α,11β-prostaglandin F2 levels were determined in the lavage fluid using immunoassays.Five minutes after the hyperpnea challenges, lung resistance increased.FK224 pretreatment inhibited the increase in a dose-dependent manner, but FK888 pretreatment had no effect.FK224 (10 mg/kg) significantly decreased lavage fluid levels of substance P and nerve growth factor; other levels were unchanged.The numbers of eosinophils and epithelial cells in the lavage fluid of the hyperpnea challenge group were increased and FK224 (10 mg/kg) was effective in reducing the eosinophil count, while FK888 had no effect on lavage fluid cell counts.We found that FK224 inhibited HIB in guinea pigs, which was mediated by neurokinin 1 and neurokinin 2 receptors with substance P and nerve growth factor in neurogenic airway inflammation.

The aim was to investigate the effects of alpha(2)-adrenoceptor antagonist yohimbine on colonic motility and defecation. The effects of yohimbine (0.5, 1.0, and 3.0 mg/kg) on colonic motility and defecation were studied in neurally intact dogs (N=6), dogs with extrinsic denervation of the ileocolon (N=4), and dogs with enterically isolated ileocolnic loops (N=5) equipped with strain gauge force transducers on the ileocolon. The effects of yohimbine on colonic motility and defecation were also studied in the presence of various antagonists (atropine, hexamethonium, ondansetron, FK224, and naloxone). Yohimbine evoked giant migrating contractions and defecation in a dose-independent manner in neurally intact dogs. These stimulatory effects of yohimbine were abolished by atropine and hexamethonium. In dogs with extrinsic denervation, yohimbine induced giant migrating contractions in the colon but did not stimulate defecation. In dogs with ileocolonic loops, yohimbine induced colonic motor complexes but not giant migrating contractions in the enterically isolated colon. These results indicate that alpha(2)-adrenoceptors in the peripheral nervous system regulate giant migrating contractions by controlling the release of acetylcholine, while those in the central nervous system must be important in the regulation of defecation.