Study objectives: Endothelin (ET)-1 is a potent
bronchoconstrictor, and asthmatics demonstrate bronchial
hyperresponsiveness to ET-1 given by inhalation. Angiotensin II (Ang
II) is increased in plasma in acute severe asthma, causes
bronchoconstriction in asthmatics, and potentiates contractions induced
by ET-1 in bovine bronchial smooth muscle in vitro, and
contractions induced by methacholine both in vitro and
in vivo. We wished to examine any potentiation of the
bronchoconstrictor activity of inhaled ET-1 by infused Ang II at
randomized placebo-controlled study.
research unit in university hospital.
asthmatic subjects with baseline FEV1 88% predicted,
bronchial hyperreactivity (geometric mean, concentration of
methacholine producing 20% fall, methacholine PC20 2.5
mg/mL), and mean age 37.1 years.
examined the effect of subbronchoconstrictor doses of infused Ang II (1
ng/kg/min and 2 ng/kg/min) or placebo on bronchoconstrictor responses
to inhaled ET-1 (dose range, 0.96 to 15.36 nmol).
Measurements: Oxygen saturation, noninvasive BP, and
spirometric measurements were made throughout the study visits. Blood
was sampled for plasma Ang II levels at baseline and before and after
Results: Ang II infusion did not
produce bronchoconstriction per se at either dose prior to
ET-1 challenge. Bronchial challenge with inhaled ET-1 produced
dose-dependent bronchoconstriction, but there was no difference in
bronchial responsiveness to ET-1 comparing infusion of placebo with Ang
II at 1 ng/kg/min or 2 ng/kg/min (geometric mean, concentration of ET-1
producing 15% fall, 5.34 nmol, 4.95 nmol, and 4.96 nmol, respectively)
(analysis of variance, p > 0.05). There was an increase in systolic
and diastolic BP at the higher dose of Ang II compared to placebo (mean
136/86 vs 117/75 mm Hg, respectively). Plasma Ang II was elevated
following infusion of both doses of Ang II compared to placebo.
Conclusions: In contrast to the potentiating effect on
methacholine-induced bronchoconstriction, Ang II at
subbronchoconstrictor doses does not potentiate ET-1-induced
bronchoconstriction in asthma.
Abbreviations: Ang II = angiotensin II;
ET-1 = endothelin-1; PC15FEV1
ET-1 = concentration of endothelin-1 producing 15% fall in
methacholine = concentration of methacholine producing 20% fall in
FEV1; RAS = renin-angiotensin system