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. I ndeed, citric acid inhalation causes bronchoconstriction in guinea pigs, bu t the mechanism of this effect has not been fully clarified. We investigate d the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid-induced bronchoconstriction in anesthetized and artificially ventilate d guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependen t increase in total pulmonary resistance (RL). Rr value obtained after 10 b reaths of citric acid inhalation was not significantly different from the v alue obtained after 20 breaths (p = 0.22). The effect produced by a half-su bmaximum dose of citric acid (5 breaths) was halved by the bradykinin B-2 r eceptor antagonist HOE 140 (0.1 mu mol.kg(-1), intravenous) and abolished b y the tachykinin NK2 receptor antagonist SR 48968 (0.3 mu mol.kg(-1), intra venous). Bronchoconstriction induced by a submaximum dose of citric acid (1 0 breaths) was partially reduced by the administration of HOE 140, SR 48968 , or the NK1 receptor antagonist CP-99,994 (8 mu mol.kg(-1) intravenous) al one 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 o f citric acid inhalation on Rr. 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 releas e from sensory nerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NO by citric acid inhalation counterac ts tachykinin-mediated bronchoconstriction. Our study suggests a possible i mplication of these mechanisms in asthma associated with gastroesophageal a cid reflux and a potential therapeutic role of tachykinin and bradykinin an tagonists.