ROLE OF NEUTRAL ENDOPEPTIDASE IN EXERCISE-INDUCED BRONCHOCONSTRICTIONIN ASTHMATIC SUBJECTS

The membrane-bound metalloproteinase, neutral endopeptidase (NEP), is a degrading enzyme of both bronchoconstrictor and bronchodilator pepti des within the airways. To examine the role of NEP in exercise-induced bronchoconstriction (EIB) in asthmatic subjects, we used inhaled thio rphan, a NEP inhibitor, as pretreatment to a B-min standardized exerci se challenge. Thirteen clinically stable asthmatic subjects participat ed in this double-blind, placebo-controlled, crossover study that was performed on 2 days separated by 48 h. Thiorphan was administered by t wo inhalations of 0.5 ml containing 1.25 mg/ml. Subsequently, exercise was performed on a bicycle ergometer at 40-50% of predicted maximal v oluntary ventilation while inhaling dry air (20 degrees C, relative hu midity 6%). The airway response to exercise was measured by forced exp iratory volume in 1 s (FEV(1)) every 3 min, up to 30 min postexercise challenge, and was expressed both as the maximal percent fall in FEV(1 ) from baseline and as the area under the time-response curve (AUG) (0 -30 min). The acute effects of both pretreatments on baseline FEV(1) w ere not different (P > 0.2), neither was there any difference in maxim al percent fall in FEV(1) between thiorphan and placebo (P > 0.7). How ever, compared with placebo, thiorphan reduced the AUC by, on average, 26% [AUG (0-30 min, +/-SE): 213.6 +/- 47.7 (thiorphan) and 288.6 +/- 46.0%fall . h (placebo); P = 0.047]. These data indicate that NEP inhi bition by thiorphan reduces EIB during the recovery period. This sugge sts that bronchodilator NEP substrates, such as vasoactive intestinal polypeptide or atrial natriuretic peptide, modulate EIB in patients wi th asthma.