Effect of Inhaled Furosemide and Bumetanide on Adenosine 5′-Monophosphate- and Sodium Metabisulfite-induced Bronchoconstriction in Asthmatic Subjects

Inhaled furosemide, a high ceiling diuretic, inhibits bronchoconstrictor responses to sodium metabisulfite (MBS) and other indirect challenges by unknown mechanisms. Furosemide acts by inhibition of Na+/Cl− transport in renal tubules and may exert similar effects on asthmatic airways. To evaluate this hypothesis we compared the effects of nebulized furosemide with those of bumetanide, another high ceiling diuretic that inhibits Na+/Cl− transport, on bronchial challenge with adenosine 5′-monophosphate (AMP) and MBS in 16 asthmatic subjects. We also studied the effects of furosemide on histamine-induced bronchoconstriction in seven of these subjects. Nine subjects inhaled furosemide (30 mg) or placebo (P) 30 min before challenge with nebulized AMP (0.39 to 400 mg/ml). Seven returned for similar study with histamine (0.125 to 32 mg/ml). In another study, seven subjects inhaled bumetanide (2 mg) or P 5 and 30 min before AMP and MBS (0.3 to 80 mg/ml) challenge. The provocative concentration causing a 20% fall in FEV1 (logPC20) was calculated by linear interpolation of log dose-response curves. Furosemide (F) significantly attenuated responses to AMP: mean ± SEM logPC20, 1.59 ± 0.24 (geometric mean PC20 [GM], 39.0 mg/ml) after F and 0.98 ± 0.29 (GM, 9.5 mg/ml) after P (p < 0.01), but it did not alter responsiveness to histamine: logPC20, 0.09 ± 0.17 (GM 1.2 mg/ml) after F and 0.09 ± 0.20 (GM, 1.2 mg/ml) after P. In contrast bumetanide (B) did not affect responses to AMP: at 5 min logPC20, 1.54 ± 0.19 (GM, 34.7 mg/ml) after B and 1.44 ± 0.15 (GM, 27.5 mg/ml) after P; at 30 min by logPC20, 1.33 ± 0.16 (GM, 21.4 mg/ml) after B, 1.17 ± 0.17 (GM, 14.8 mg/ml) after P, or to MBS: 0.83 ± 0.13 (GM, 6.8 mg/ml) after B and 0.80 ± 0.11 (GM, 6.3 mg/ml) after P. Thus, F inhibits airway responses to AMP by an action that is unlikely to involve airway smooth muscle as histamine-induced bronchoconstriction is unaffected. The degree of protection is comparable to that observed in our previous study with MBS challenge. Bumetanide, another loop diuretic, fails to inhibit either AMP or MBS bronchoconstriction, suggesting that the protective effect of furosemide is independent of Na+/Cl− inhibition.