ET-1-induced bronchoconstriction is mediated via ETB receptor in mice.
Endothelin (ET)-1 is one of the most potent agonists of airway smooth muscle and can act via two different ET receptor subtypes, i.e., ETA and ETB. To determine the effects of ET-1 on in vivo pulmonary function and which ET receptors are involved in murine lungs, we investigated 1) the effects of ET and sarafotoxin S6c (S6c), a selective ETB agonist, on pulmonary function and 2) the effects of BQ-123 and BQ-788, specific ETA- and ETB-receptor antagonists, on ET-1-induced bronchoconstriction. ICR mice were anesthetized and mechanically ventilated (frequency = 2.5 Hz, tidal volume = 8 ml/kg, positive end-expiratory pressure = 3 cmH2O). Intravenous ET-1, ET-2, and ET-3 increased lung resistance similarly and equipotently, whereas S6c elicited a greater degree of bronchoconstriction. Mice were then pretreated with saline (Sal), BQ-123 (0.2, 1, and 5 mg/kg), or BQ-788 (0.2, 1, and 5 mg/kg) before administration of ET-1 (10(-7) mol/kg iv). No dose of BQ-123 blocked ET-1-induced constriction, whereas pretreatment with each dose of BQ-788 significantly inhibited ET-1-induced responses. There were significant differences in morphometrically assessed airway constriction between Sal and BQ-788 and between BQ-123 and BQ-788, whereas no significant difference was observed between Sal and BQ-123. There were no significant morphometric differences in the airway wall area among the three groups. These observations suggest that the ETB- but not ETA-receptor subtype may mediate the changes in murine pulmonary function in response to ET-1. In addition, the ETB-receptor antagonist reduces ET-1-induced airway narrowing by affecting airway smooth muscle contraction in mice.
Nagase
T
T
Department of Geriatrics, Faculty of Medicine, University of Tokyo, Tokyo 113, Japan.
Aoki
T
T
Oka
T
T
Fukuchi
Y
Y
Ouchi
Y
Y
D000818:Animals; D001980:Bronchi / Q000033:anatomy & histology / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D019333:Endothelin-2 / Q000494:pharmacology; D019334:Endothelin-3 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000819:agonists / Q000502:physiology*; D012129:Respiratory Function Tests; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)