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Effect of Infused Angiotensin II on the Bronchoconstrictor Activity of Inhaled Endothelin-1 in Asthma^*

^* From the Department of Respiratory Medicine, West Glasgow Hospitals University NHS Trust, Glasgow, Scotland, UK. Supported by grants from Chest Heart & Stroke Scotland and the National Asthma Campaign (UK).

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 subbronchoconstrictor doses.

Design: Double-blind randomized placebo-controlled study.

Setting: Asthma research unit in university hospital.

Patients: Eight 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.

Interventions: We 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 ET-1 inhalation.

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.

Key Words: angiotensin • asthma • bronchoconstriction • endothelin

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