Am. J. Respir. Crit. Care Med., Volume 157, Number 2, February 1998, 560-564

Airway Hyperresponsiveness to Methacholine in Mutant Mice Deficient in Endothelin-1

TAKAHIDE NAGASE, HIROKI KURIHARA, YUKIKO KURIHARA, TOMOKO AOKI, YOSHINOSUKE FUKUCHI, YOSHIO YAZAKI, and YASUYOSHI OUCHI

Department of Geriatrics, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Endothelin-1 (ET-1) has recently been reported to have a potential pathophysiologic role in bronchial asthma. In the current study, we hypothesized whether ET-1 and a gene encoding ET-1 might be involved in airway hyperresponsiveness (AHR), which is a major feature of bronchial asthma. To test this hypothesis, we investigated airway responsiveness in ET-1^+/ heterozygous knockout mice, which genetically produce lower levels of ET-1, and in ET-1^+/+ wild-type mice. Airway responsiveness was assessed through the concentration of an agonist required to double lung resistance (EC₂₀₀ RL). Unexpectedly, airway responsiveness to methacholine was markedly enhanced in ET-1^+/ heterozygous mice as compared with ET-1^+/+ wild-type mice (EC₂₀₀ RL: 1.8 ± 0.1 versus 21.6 ± 5.6 mg/ml, p < 0.002). Pretreatment with the nitric oxide (NO) synthase inhibitor N^g-monomethyl-L-arginine (L-NMMA) significantly enhanced methacholine responsiveness in ET-1^+/+ wild-type mice, but not in ET-1^+/ heterozygous mice. Meanwhile, there was no difference between ET-1^+/ heterozygous mice and the wild-type mice in airway responsiveness to 5-hydroxytryptamine (5-HT). In sensitized mice, no significant differences in responsiveness to antigen were observed between the two groups. These findings suggest that the gene encoding ET-1 may be potentially involved in the etiology of airway hyperreactivity, and that the decrease in ET-1 concentration is associated with AHR to methacholine. In mice, ET-1 as well as NO may have a significant role in the homeostasis of airway physiology.

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