Effect of Inhaled Furosemide on Metabisulfite- and Methacholine-induced Bronchoconstriction and Nasal Potential Difference in Asthmatic Subjects

To evaluate the hypothesis that furosemide inhibits indirect bronchoconstrictor challenges by altering airway epithelial ion transport, we studied its effects on indirect bronchoconstriction induced by inhaled metabisulfite (MBS) and nasal potential difference (PD) in seven subjects with mild asthma. Its effect on direct bronchoconstriction by the inhaled muscarinic agonist methacholine (MC) was studied in six of these subjects. Each subject inhaled furosemide, 30 mg, in a randomized, double-blind, placebo-controlled fashion immediately before challenge with MBS (0.3 to 160 mg/ml in increasing doubling concentrations) and, in another study, MC (0.125 to 32 mg/ml) aerosols from a nebulizer attached to a dosimeter. PC20MBS and PC20MC, the concentration of each agent needed to lower FEV1 by 20%, were calculated by linear interpolation of the log dose-response curves. Furosemide had no effect on resting lung function, but it caused a significant threefold reduction in sensitivity to MBS (PC20MBS: GM ± GSEM, 15.1 ± 1.6 mg/ml after placebo and 40.7 ± 1.7 mg/ml after furosemide; p < 0.001) with a protective index of 64.8 ± 10.7%. Furosemide caused no change in sensitivity to MC (PC20 MC: GM ± GSEM, 2.37 ± 1.61 mg/ml after placebo and 2.19 ± 1.751 mg/ml after furosemide; NS). In a third study, furosemide, 30 mg, and placebo were inhaled through the nose in a randomized double-blind fashion immediately prior to inhalation of a PC20 concentration of MBS through the nose. Nasal PD was measured before and after placebo or furosemide, and again after MBS inhalation. Neither placebo nor furosemide had any effect on nasal PD compared with the same-day baseline; likewise, MBS had no effect on nasal PD whether preceded by placebo or furosemide. A positive control, 10−3 M amiloride inhaled nasally using the same apparatus, reduced nasal PD by 36.3 ± 5.4% in six normal subjects (p < 0.05). We conclude that inhaled furosemide inhibits MBS-induced bronchoconstriction but does not directly reduce smooth-muscle contractility or affect electrogenic epithelial ion transport. The mechanism whereby furosemide protects against MBS challenge remains uncertain.