Role of bradykinin and tachykinins in the potentiation by enalapril of coughing induced by citric acid in pigs.

Angiotensin-converting enzyme (ACE) inhibitors are among the first-choice drugs for treating hypertension and congestive heart disease. It has been reported, however, that these drugs could induce chronic cough and airway hyperresponsiveness. The aim of this work was to assess in pigs the effects of bradykinin and tachykinins on citric-acid-induced coughing after ACE inhibitor pretreatment. Coughing was induced by challenging pigs with an aerosol of 0.8 M citric acid over 15 min. Coughs were counted by a trained observer for 30 min. The animals underwent two cough induction tests two days apart (days 1 and 3), the first being taken as a control. All drugs were injected intravenously 30 min before the second challenge. In the control group, no difference was observed between days 1 and 3. The ACE inhibitor enalapril (7.5 and 15 microg/kg) caused the cough frequency to increase significantly. In contrast, a dose-related decrease was observed with Hoe140 (icatibant), a bradykinin B2 receptor antagonist (0.5 and 1 mg/kg). When both drugs were administered simultaneously (15 microg/kg for enalapril and 1 mg/kg for Hoe140), a significant increase was observed as compared with the control value obtained on day 1. When enalapril was combined with the three tachykinin receptor antagonists SR 140333 (NK1 receptor antagonist), SR 48968 (NK2 receptor antagonist) and SR 142801 (NK3 receptor antagonist), a significant decrease was observed as compared with control value obtained on day 1; the percentage of variation was also significantly different as compared with those observed in enalapril groups at both doses. These data suggest that ACE-inhibitor-induced enhancement of the cough reflex is mainly due to tachykinins and not to bradykinin in our pig model. Bradykinin, however, plays a major role in coughing induced by citric acid alone.