Effect of endotoxin and platelet-activating factor on rat vascular permeability: role of vasoactive mediators.
The contribution of several vasoactive mediators such as histamine, serotonin, bradykinin, arachidonic acid metabolites and PAF to vascular permeability changes was determined in a rat model of acute endotoxemia. Lipopolysaccharide (10-40 mg/kg, i.v.) from E. coli 0127:B8 (LPS) elicited an increase in Evans blue extravasation in trachea, thymus, seminal vesicle and stomach, whereas other organs remained unaffected. LPS (25 mg/kg)-induced extravasation was not inhibited by intravenous pretreatment with histamine (H1) antagonist mepyramine (5 mg/kg) or bradykinin (B2) antagonist HOE-140 (0.1 mg/kg), whereas other standard drugs selectively inhibited leakage in particular tissues, e.g. the cyclooxygenase inhibitor indomethacin (5 mg/kg) in trachea (78%) and seminal vesicle (64%), the serotonin and H1 antagonists cyproheptadine (2 mg/kg) in trachea (88%) and stomach (56%) and the dual cyclooxygenase/lipoxygenase inhibitor phenidone (10 mg/kg) in seminal vesicle (87%). PAF antagonists lexipafant and UR-12460 (10 mg/kg), but not apafant, potently inhibited extravasation in trachea (59, 84%) and seminal vesicle (81, 78%) and in stomach only UR-12460 (52%), whereas all of them were ineffective in thymus. When extravasation was induced by PAF (4 micrograms/kg) a low dose (0.1 mg/kg) of the three PAF antagonists strongly reduced extravasation in thymus and seminal vesicle, whereas lexipafant and UR-12460 did so in trachea (82, 100%) and only lexipafant in stomach (100%). Mepyramine, cyproheptadine, HOE-140 and indomethacin did not inhibit the effect of PAF, whereas phenidone inhibited it by 58% in trachea. These results suggest that most of the LPS-induced increase in vascular permeability is mediated by secondary vasoactive mediators among which PAF plays a pivotal role, although their relative contribution may vary from tissue to tissue.
Balsa
D
D
Department of Pharmacology, J. Uriach & Cia Laboratories, Barcelona, Spain.
Merlos
M
M
Giral
M
M
Ferrando
R
R
Garcia-Rafanell
J
J
Forn
J
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005122:Exudates and Transudates / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D007093:Imidazoles; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D010879:Piperazines; D010972:Platelet Activating Factor; D011720:Pyrazoles; C094033:UR 12460; D007930:Leucine; C015429:phenidone; C103289:lexipafant; D007213:Indomethacin