cp-99994 and Asthma

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.

Topics: Adult; Airway Resistance; Asthma; Bronchoconstriction; Cough; Cross-Over Studies; Double-Blind Method; Humans; Male; Middle Aged; Piperidines; Respiratory Function Tests; Saline Solution, Hypertonic; Stereoisomerism

Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalation causes bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fully clarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid- induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependent increase in total pulmonary resistance (RL). RL value obtained after 10 breaths of citric acid inhalation was not significantly different from the value obtained after 20 breaths (p = 0.22). The effect produced by a half-submaximum dose of citric acid (5 breaths) was halved by the bradykinin B2 receptor antagonist HOE 140 (0.1 micromol x kg-1, intravenous) and abolished by the tachykinin NK2 receptor antagonist SR 48968 (0.3 micromol x kg-1, intravenous). Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK1 receptor antagonist CP-99,994 (8 micromol x kg-1, intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994. Pretreatment with the NO synthase inhibitor, L-NMMA (1 mM, 10 breaths every 5 min for 30 min) increased in an L-arginine-dependent manner the effect of citric acid inhalation on RL. HOE 140 and CP-99,994 markedly reduced the L-NMMA-potentiated bronchoconstriction to inhaled citric acid. We conclude that citric acid-induced bronchoconstriction is caused by tachykinin release from sensory nerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NO by citric acid inhalation counteracts tachykinin-mediated bronchoconstriction. Our study suggests a possible implication of these mechanisms in asthma associated with gastroesophageal acid reflux and a potential therapeutic role of tachykinin and bradykinin antagonists.

Topics: Administration, Inhalation; Adrenergic beta-Antagonists; Airway Resistance; Animals; Asthma; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Citric Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Male; Nitric Oxide Synthase; omega-N-Methylarginine; Piperidines; Receptors, Neurokinin-2