Neutral endopeptidase inhibitor thiorphan increases airway narrowing to inhaled sodium metabisulfite in normal subjects.
Possible mechanisms involved in inhaled sodium metabisulfite (MBS)-induced bronchoconstriction include cholinergic reflex and release of tachykinins from sensory nerve endings. Tachykinins are potent bronchoconstrictors cleaved and inactivated by neutral endopeptidase (NEP) in the airways. To investigate the role of tachykinins in airway response to MBS, we assessed the effect of NEP-inhibitor thiorphan on airway response to MBS in nine nonatopic, nonasthmatic subjects. Two inhalational challenges with doubling doses of MBS (0.03 to 16 mumol) were performed 3 d apart. Ten minutes before MBS challenge, subjects randomly inhaled either thiorphan (1.25 mg) or placebo according to a double-blind cross-over design. Airflow at 30% of vital capacity (V30p) from partial expiratory flow-volume curves was measured at baseline, 10 min after thiorphan or placebo, and 2 min after each MBS dose. The dose of MBS causing 40% fall in V30p (PD40V30p) was calculated. Neither thiorphan nor placebo affected baseline airway caliber. Thiorphan caused a leftward shift of the dose-response curve to MBS. After placebo a measurable PD40V30p was obtained in four of nine subjects. In these subjects PD40V30p fell significantly after thiorphan inhalation. Four of five subjects who did not exhibit PD40V30p after placebo showed measurable PD40V30p after thiorphan. Percent fall in V30p caused by highest dose of MBS was significantly greater after thiorphan compared with placebo (55.9 +/- 4.6% versus 30.8 +/- 5.6%; mean +/- SE; p < 0.001). Results of this study demonstrate that the NEP-inhibitor thiorphan increases MBS-induced bronchoconstriction in normal subjects, suggesting that tachykinins are involved in airway responses to inhaled MBS.
Bellofiore
S
S
Istituto di Malattie Respiratorie, Università di Catania, Italy.
Caltagirone
F
F
Pennisi
A
A
Ciancio
N
N
Mistretta
A
A
Di Maria
G U
GU
D000328:Adult; D000336:Aerosols; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004357:Drug Synergism; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012016:Reference Values; D012129:Respiratory Function Tests; D013447:Sulfites / Q000008:administration & dosage*; D015244:Thiorphan / Q000008:administration & dosage*; D013997:Time Factors
D000336:Aerosols; D016085:Bronchoconstrictor Agents; D013447:Sulfites; C005200:sodium metabisulfite; D015244:Thiorphan; D015260:Neprilysin