The role of neutral endopeptidase in exercise-induced
bronchoconstriction in asthmatic subjects.
Gouw, Heidi W. F. M. De, Zuzana Diamant, Eugenie A. P. Kuijpers, Jacob
K. Sont, Peter J. Sterk.
Department of Pulmonology, Department of Clinical Chemistry,
Pharmacy and Toxicology, Leiden University Hospital, 2300 RC Leiden,
The Netherlands
APStracts 3:0198A, 1996.
The membrane-bound metalloproteinase, neutral endopeptidase (NEP) is a
degrading enzyme of both bronchoconstrictor and bronchodilator
peptides within the airways. To examine the role of NEP in exercise
-induced bronchoconstriction (EIB) in asthmatics, we used inhaled
thiorphan, a NEP inhibitor, as pretreatment to a 6 minute
standardized exercise challenge. Thirteen clinically stable asthmatic
subjects participated in this double-blind, placebo-controlled,
cross-over study which was performed on two days separated by 48 h.
Thiorphan was administered by 2 inhalations of 0.5 ml containing 1.25
mg/ml. Subsequently, exercise was performed on a bicycle ergometer at
40-50% of predicted maximum voluntary ventilation while inhaling dry
air (20 degrees C, RH 6%). The airway response to exercise was
measured by FEV1, every 3 minutes up to 30 minutes post-exercise
challenge, and was expressed both as the maximal %fall in FEV1 from
baseline and as the area under the time-response curve (AUC) (0-30
min). The acute ef fects of both pretreatments on baseline FEV1 were
not different (p >0.2), neither was there any difference in
maximal %fall in FEV1 between thiorphan and placebo (p >0.7).
However, as compared to placebo, thiorphan reduced the AUC by on
average 26% (AUC (0-30 min) +/- SEM: 213.6 +/- 47.7 (thiorphan) and
288.6 +/- 46.0 (placebo) %fall x h; p=0.047). These data indicate
that NEP-inhibition by thiorphan reduces EIB during the recovery
period. This suggest that bronchodilator NEP-substrates, such as
vasoactive intestinal peptide (VIP) or atrial natriuretic peptide
(ANP), modulate EIB in patients with asthma.
Received 28 July 1995; accepted in final form 14 March 1996.
APS Manuscript Number A827-5.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 23 April 96