Bronchoconstriction induced by citric acid inhalation in guinea pigs : Role of tachykinins, bradykinin, and nitric oxide

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.