Endothelin-1-induced bronchoconstriction in asthma.
Endothelin-1 (ET-1) has been indirectly implicated in the pathophysiology of asthma, and it is a potent bronchoconstrictor both in vitro and by inhalation in animal models in vivo. We examined the effect of inhaled ET-1 on airway tone in comparison with methacholine in eight asthmatics and five healthy volunteers in a double-blind randomized fashion. After a screening methacholine challenge each asthmatic had two ET-1 (doubling dose range, 0.96 to 15.36 nmol) and one methacholine (doubling dose range, 0.33 to 21.0 mumol) challenge, and normal subjects had a single ET-1 challenge. Inhalations were delivered using a dosimeter, and lung function measurements were made using constant-volume body plethysmography, with end points being a 35% fall in specific airway conductance (SGaw) and a 15% fall in FEV1. Samples for plasma ET-1 were taken before and after the inhalations, and pulse, blood pressure and oxygen saturation were monitored throughout the inhalations. All the asthmatic subjects displayed rapid-onset (< 5 min) dose-dependent bronchoconstriction to ET-1 across the dose range used, with mean (range) ET-1 PC35SGaw values of 5.15 (1.4 to 13.9) nmol, and 4.3 (1.2 to 8.3) nmol for the two ET-1 inhalations, and 0.42 (0.2 to 0.7) mumol for methacholine. Albuterol completely and rapidly reversed ET-1-induced bronchoconstriction, and in two patients not given albuterol, bronchoconstriction lasted 60 to 90 min. No significant bronchoconstriction was observed in any of the healthy volunteers across the ET-1 dose range used (mean PC35SGaw > 15.36 nmol). Oxygen saturation did not alter in either group, and plasma ET-1 did not change after ET-1 inhalation. Noninvasive blood pressure measurements revealed a fall in systolic blood pressure in normal subjects, with no change in asthmatics. Endothelin-1 is a potent bronchoconstrictor in asthma, with a bronchoconstrictor potency around 100 times that of methacholine in asthma. Asthmatics exhibit bronchial hyperreactivity to ET-1, and inhaled ET-1 can safely be given to asthmatics and normal subjects in the nebulized dose range 0.96 to 15.36 nmol.
Chalmers
G W
GW
Department of Respiratory Medicine, West Glasgow Hospitals University NHS Trust, United Kingdom.
Little
S A
SA
Patel
K R
KR
Thomson
N C
NC
D000328:Adult; D000336:Aerosols; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage* / Q000097:blood; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D008875:Middle Aged; D012129:Respiratory Function Tests / Q000706:statistics & numerical data; D016037:Single-Blind Method; D018709:Statistics, Nonparametric; D013997:Time Factors
D000336:Aerosols; D016085:Bronchoconstrictor Agents; D019332:Endothelin-1; D016210:Methacholine Chloride