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.