FK-224

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.

Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged nonproductive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity, and slightly increased bronchial responsiveness. Animal model of cough variant asthma has not been reported. The aim of this study was to establish an animal model for studying detailed pathophysiology of cough variant asthma. Bronchial responsiveness to methacholine and cough reflex sensitivity to capsaicin were measured 72 hours after antigen (ovalbumin, OA) inhalation in actively sensitized guinea pigs. Next, cough number and specific airway resistance (sRaw) were measured during 20 minutes following reinhalation of OA solution, which was carried out 72 hours after the first OA inhalation, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALE) were measured. Bronchial responsiveness to methacholine, but not cough reflex sensitivity to capsaicin, was significantly increased 72 hours after the first inhalation of OA solution. Number of coughs, sRaw and total cell number in BALF increased significantly by the OA reinhalation, and the cough number and the increase in sRaw were significantly suppressed by beta2 agonist, procaterol. FK224, a specific neurokinin (NK) receptor antagonist, did not significantly influence the OA reinhalation-induced cough and increase in sRaw and total cell number in BALF in this model In conclusion, pathophysiologic feature of this animal model is similar to that of clinical cough variant asthma. Tachykinins may not play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.