Endothelin-1-induced Bronchoconstriction in Asthma

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Abstract
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.