title: A thromboxane mimetic, U-46619, produces plasma exudation in airways of the guinea pig.
abstract: Thromboxane A2 (TxA2) has been implicated in airway responses to allergen and in the bronchial hyperresponsiveness observed in asthma. Furthermore a TxA2 receptor antagonist and a TxA2 synthase inhibitor inhibit plasma exudation in airways induced by inhaled platelet-activating factor. To evaluate whether TxA2 has any direct effect on plasma exudation in the airways, we studied the effect of a stable TxA2 mimetic (U-46619; 2, 20, and 200 nmol/kg iv) on lung resistance (RL) and Evans blue dye extravasation (marker of plasma albumin; 20 mg/kg iv) at the airway levels of trachea, main bronchi, and proximal and distal intrapulmonary airways in anesthetized, tracheostomized, and mechanically ventilated guinea pigs. Injection of U-46619 produced an immediate and marked dose-dependent increase in RL, which peaked at approximately 30 s. At the highest dose of U-46619, we also observed a later increase in RL, starting at approximately 3 min and reaching a second peak at approximately 8 min. Mean systemic blood pressure increased in a dose-dependent manner [maximum 82 +/- 8 (SE) mmHg]. U-46619 also produces dose-dependent plasma exudation, measured as Evans blue dye extravasation, at all airway levels as well as into the tracheal lumen. Airway responses to U-46619 (200 nmol/kg iv) were abolished in animals pretreated with the TxA2 receptor antagonist ICI-192605 (0.5 mg/kg iv). We conclude that U-46619, despite being a vasoconstrictor, is potent in inducing plasma exudation in airways and that this effect is mediated via a TxA2 receptor.
authors.affiliation: Department of Thoracic Medicine, Royal Brompton National Heart and Lung Hospital, London, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Lötvall
authors.forename: W
authors.initials: W
authors.lastname: Elwood
authors.forename: K
authors.initials: K
authors.lastname: Tokuyama
authors.forename: T
authors.initials: T
authors.lastname: Sakamoto
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: K F
authors.initials: KF
authors.lastname: Chung
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000403:Airway Resistance / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000503:physiopathology; D004146:Dioxanes / Q000494:pharmacology; D005122:Exudates and Transudates / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D010949:Plasma / Q000187:drug effects* / Q000502:physiology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane; D012143:Respiratory Physiological Phenomena; D012137:Respiratory System / Q000098:blood supply / Q000187:drug effects*; D013928:Thromboxane A2 / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004146:Dioxanes; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C057498:ICI 192605; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid