The effect of the selective PAF antagonist CIS-19 on PAF- and antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity in guinea-pigs.
We investigated the effects of a novel platelet-activating factor (PAF) receptor antagonist, CIS-19 [cis-2-(3, 4-dimethoxyphenyl)-6-isopropoxy-7-methoxy-1-(N-methyl-formamido)-1, 2, 3, 4-tetrahydronaphthalene], on PAF-, histamine-, substance P- and antigen-induced bronchoconstriction and microvascular leakage, as well as PAF- and antigen-induced bronchial hyperreactivity to methacholine in urethane-anesthetized guinea-pigs. Administration of CIS-19 (0.5-5 mg/kg, i.v.) inhibited the increase in lung resistance induced by PAF (30 ng/kg, i.v.) in a dose-dependent manner, but failed to inhibit the increase induced by histamine (30 micrograms/kg, i.v.) or substance P (6.5 micrograms/kg, i.v.). CIS-19 (5 mg/kg, i.v.) did not inhibit the increase in lung resistance induced by ovalbumin (2 mg/kg, i.v.) in actively sensitized guinea-pigs. PAF (30 ng/kg, i.v.)-induced microvascular leakage, measured by the extravasation of Evans blue dye, was dose-dependently inhibited by CIS-19 (0.5-5 mg/kg, i.v.) in the trachea, main bronchi and intrapulmonary airways, but it did not affect histamine (30 micrograms/kg, i.v.)- or substance P (6.5 micrograms/kg, i.v.)-induced microvascular leakage at all airway levels. CIS-19 (2.5 and 5 mg/kg) did not affect ovalbumin (2 mg/kg, i.v.)-induced microvascular leakage in all airway levels in actively sensitized guinea-pigs, CIS-19 (2.5 and 5 mg/kg, i.v.) significantly inhibited PAF-induced enhancement of the bronchial response to methacholine, but had no effect on ovalbumin (0.05 mg/kg, i.v.)-induced bronchial hyperreactivity in actively sensitized guinea-pigs. It is concluded that CIS-19 is a potent PAF receptor antagonist which inhibits PAF- but not antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity. These results suggest that PAF plays little or no role in early airway responses following antigen challenge.
Lin
C H
CH
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Ko
F N
FN
Ishii
H
H
Ishikawa
T
T
Chen
I S
IS
Teng
C M
CM
Kuo
H P
HP
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000941:Antigens / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000276:immunology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000633:toxicity; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051381:Rats; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D013373:Substance P / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000941:Antigens; D016085:Bronchoconstrictor Agents; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013764:Tetrahydronaphthalenes; C039351:platelet activating factor receptor; D016210:Methacholine Chloride; D013373:Substance P; D006632:Histamine; C079137:CIS 19