EFFECT OF ACETAZOLAMIDE ON COUGH INDUCED BY LOW-CHLORIDE-ION SOLUTIONS IN NORMAL SUBJECTS - COMPARISON WITH FUROSEMIDE

Background: The antitussive activity of inhaled fuorsemide has been at tributed to its blocking effect on the Na+-2Cl(-)-K+ cotransporter. It is likely that the antitussive activity of inhaled diuretics is more complex because amiloride, a diuretic that has no effect on the Na+-2C l(-)-K+ cotransporter, also shows a significant effect against cough i nduced by low-chloride-ion solutions. Apart from pharmacokinetics of i nhaled diuretics, this activity could also depend on the inhibition of carbonic anhydrase. Objectives: We therefore studied the effect of in haled acetazolamide, a selective inhibitor of carbonic anhydrase activ ity, on cough induced by the inhalation of different chloride ion solu tions in a group of normal subjects. This was compared with the antitu ssive effect of furosemide. In addition, we attempted to determine whe ther the effect of acetazolamide is dose-dependent. Methods: Cough cha llenge consisted of consecutive inhalations of four solutions having d ecreasing concentrations of chloride ions (150, 75, 37.5 and 0 mmol/L) . Nine normal subjects underwent the cough challenge 5 minutes after t he inhalation of saline placebo, azetazolamide (500 mg), and furosemid e (30 mg) according to a randomized, double-blind study design. A grou p of six subjects were challenged according to the same procedure and study design, after the inhalation of saline placebo and of two doses of acetazolamide (250 mg and 500 mg). Results: Inhaled acetazolamide s ignificantly reduced cough response to 37.5 and 0 mmol/L chloride solu tions compared with placebo (p < 0.015 and p < 0.015, respectively). F urosemide showed a similar protective effect (p < 0.015 and p < 0.025, respectively). Acetazolamide provided a significantly better protecti ve effect than furosemide (p < 0.025 and p < 0.015, respectively). The antitussive activity of the two doses of acetazolamide was not statis tically different. Conclusion: These results demonstrate that inhaled acetazolamide, a selective inhibitor of carbonic anhydrase, attenuates cough induced by low-chloride-ion solutions in normal subjects. At th e applied doses, its antitussive activity is slightly greater than fur osemide. This finding suggests that the inhibition of carbonic anhydra se activity is likely involved in modulating changes caused by absence of a chloride ion in the airway microenvironment of human beings.