Effect of infused angiotensin II on the bronchoconstrictor activity of inhaled endothelin-1 in asthma

Study objectives: Endothelin (ET)-1 is a potent bronchoconstrictor, and ast hmatics demonstrate bronchial hyperresponsiveness to ET-1 given by inhalati on. Angiotensin II (Ang II) is increased in plasma in acute severe asthma, causes bronchoconstriction in asthmatics, and potentiates contractions indu ced by ET-1 in bovine bronchial smooth muscle in vitro, and contractions in duced by methacholine both in vitro and in vivo. We wished to examine any p otentiation of the bronchoconstrictor activity of inhaled ET-1 by infused A ng 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, bronch ial hyperreactivity (geometric mean, concentration of methacholine producin g 20% fall, methacholine PC20 2.5 mg/mL), and mean age 37.1 years. Interventions: We examined the effect of subbronchoconstrictor doses of inf used 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 measuremen ts 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 eith er dose prior to ET-1 challenge. Bronchial challenge with inhaled ET-1 prod uced dose-dependent bronchoconstriction, but there was no difference in bro nchial 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 potent iate ET-l-induced bronchoconstriction in asthma.