Mediator involvement in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitized Brown Norway rats.
1. To determine which mediators are involved in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitised Brown Norway rats we investigated the effect of a histamine H(1) receptor antagonist, mepyramine, a 5-HT receptor antagonist, methysergide, and a cys-leukotriene-1 receptor antagonist, montelukast. 2. Ovalbumin at 1 mg kg(-1) i.v. caused a significant increase in microvascular leakage in the airways and at 3 mg kg(-1) i.v. caused a significant increase in airways resistance. 3. Histamine (1 mg kg(-1) i.v.), 5-HT (0.1 mg kg(-1) i.v.) and leukotriene D(4) (LTD(4), 50 microg kg(-1) i.v.) caused a significant increase in microvascular leakage in the airways. 4. Mepyramine (1 mg kg(-1) i.v.), methysergide (0.1 mg kg(-1) i.v.), or montelukast (30 mg kg(-1) i.v.) inhibited histamine, 5-HT or LTD(4) -induced microvascular leakage respectively. 5. Methysergide (0.1 mg kg(-1) i.v.) reduced ovalbumin-induced microvascular leakage in the trachea and at 0.3 mg kg(-1) i.v. inhibited bronchospasm (38 and 58%, respectively). Montelukast (30 mg kg(-1) p.o.) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (78%) and inhibited ovalbumin-induced bronchospasm (50%). Mepyramine (3 mg kg(-1) i.v.) had no effect on ovalbumin-induced leakage or bronchospasm. 6. A combination of all three compounds (mepyramine, methysergide and montelukast) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (70 - 78%) and almost completely inhibited bronchospasm (92%). 7. Antigen-induced bronchospasm appears to equally involve the activation of 5-HT and cys-leukotriene-1 receptors whereas ovalbumin-induced microvascular leakage appears to be predominantly mediated by cys-leukotriene-1 receptors.
Hele
D J
DJ
Respiratory Pharmacology Group, Department of Cardiothoracic Surgery, Imperial College School of Medicine, National Heart & Lung Institute, Dovehouse Street, Chelsea, London SW3 6LY.
Birrell
M A
MA
Webber
S E
SE
Foster
M L
ML
Belvisi
M G
MG
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D001986:Bronchial Spasm / Q000503:physiopathology*; D002199:Capillary Permeability / Q000502:physiology; D003521:Cyclopropanes; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D017998:Leukotriene D4 / Q000494:pharmacology; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology*; D011738:Pyrilamine / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D012130:Respiratory Hypersensitivity / Q000503:physiopathology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013440:Sulfides; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D006634:Histamine H1 Antagonists; D011804:Quinolines; D012702:Serotonin Antagonists; D013440:Sulfides; D012701:Serotonin; D017998:Leukotriene D4; D006632:Histamine; D010047:Ovalbumin; D011738:Pyrilamine; C093875:montelukast; D008784:Methysergide