EFFECT OF DIURETICS ON ALLERGEN-INDUCED CONTRACTIONS OF PASSIVELY SENSITIZED HUMAN BRONCHI IN-VITRO

inhaled furosemide has been shown to protect subjects with asthma from bronchoconstriction induced by a wide variety of stimuli, including a llergen, but the mechanism of action is controversial. We have used an in vitro model of allergen-induced bronchoconstriction to examine the effects of furosemide and other ion transport inhibitors. Human bronc hial rings were passively sensitized by incubation with serum from an atopic donor and were challenged with Dermatophagoides pteronyssinus. Allergen-challenged bronchial rings developed bronchoconstriction whic h was effectively inhibited by the cysteinyl-leukotriene antagonist IC I 198,615 (10(-7) M) and to a lesser extent by terfenadine (10(-5) M). Assessed over 60 min furosemide 10(-6), 10(-5), and 10(-4) M inhibite d contractions by a mean (95% confidence interval [CI]) 7.9% (-23.5, 3 9.3%, p > 0.05), 44.2% (12.9, 75.2%, p < 0.01), and 86.9% (55.5, 118.3 %, p < 0.001) respectively (n = 5). The same concentrations of bumetan ide inhibited contractions by 21.5% (-8.4, 51.4%, p > 0.05), 13.6% (-1 6.3, 43.4%, p > 0.05) and 51.6% (21.7, 81.4%, p < 0.01) respectively ( n = 5). The sodium transport inhibitor amiloride and the anion transpo rt inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) w ere without effect (both 10(-4) M; n = 4). Furosemide increased PGE(2) production by the bronchial rings by 134% (95% CI 53, 259%). Indometh acin (3 x 10(-6) M) blocked the furosemide-induced increase in PGE(2) production and reduced the protection afforded by 10(-4) M furosemide against allergen-induced contractions from 67.9% to 34.7% (mean differ ence 33.2%; 95% CI 9.7, 56.6%; p < 0.01; n = 8). PGE(2) (10(-7), 10(-6 ), and 10(-5) M) did not alter airway smooth muscle responsiveness to methacholine but inhibited allergen-induced contractions by 5% (-68.2, 78.3%), 14.5% (-58.8, 87.7%), and 100% (26.7, 173.2%; p < 0.02) respe ctively (n = 5). Thus furosemide and to a lesser extent bumetanide inh ibit allergen-induced contractions of passively sensitized human bronc hi. Production of PGE(2) may play a role in the inhibitory effect of f urosemide.