Effect of a Paf antagonist, WEB 2086, on airway microvascular leakage in the guinea-pig and platelet aggregation in man.
1. The triazolodiazepine WEB 2086 has been evaluated as an antagonist of platelet-activating factor (Paf) by studying its effects on Paf-induced human platelet aggregation and microvascular leakage in guinea-pigs. 2. WEB 2086 inhibited Paf-induced platelet aggregation in platelet-rich plasma in vitro (IC50 = 117 +/- 35 nM, mean +/- s.d.) but had no effect on adenosine 3',5'-diphosphate-induced aggregation. 3. Paf-induced microvascular leakage, measured by the extravasation of intravenously-injected Evans blue dye, was inhibited in a dose-related fashion in the airways and other tissues by WEB 2086, achieving a maximal inhibitory effect at 10 micrograms kg-1, i.v. 4. However, WEB 2086 (10 micrograms kg-1, i.v.) did not inhibit a comparable increase in vascular permeability induced by ovalbumin in sensitized guinea-pigs. 5. We conclude that WEB 2086 is a potent antagonist of Paf and that Paf does not appear to be responsible for antigen-induced microvascular leakage.
Evans
T W
TW
Department of Clinical Pharmacology, Brompton Hospital, London.
Dent
G
G
Rogers
D F
DF
Aursudkij
B
B
Chung
K F
KF
Barnes
P J
PJ
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects*; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles
D001381:Azepines; D010972:Platelet Activating Factor; D014227:Triazines; D014230:Triazoles; C052518:WEB 2086; D000244:Adenosine Diphosphate; D010047:Ovalbumin