EFFECT OF ENDOTOXIN AND PLATELET-ACTIVATING-FACTOR ON RAT VASCULAR-PERMEABILITY - ROLE OF VASOACTIVE MEDIATORS

The contribution of several vasoactive mediators such as histamine, se rotonin, bradykinin, arachidonic acid metabolites and PAF to vascular permeability changes was determined in a rat model of acute endotoxemi a. Lipopolysaccharide (10-40 mg/kg, i.v.) from E. coli 0127:B8 (LPS) e licited an increase in Evans blue extravasation in trachea, thymus, se minal vesicle and stomach, whereas other organs remained unaffected. L PS (25 mg/kg)-induced extravasation was not inhibited by intravenous p retreatment with histamine (H-1) antagonist mepyramine (5 mg/kg) or br adykinin (B-2) antagonist HOE-140 (0.1 mg/kg), whereas other standard drugs selectively inhibited leakage in particular tissues, e.g. the cy clooxygenase inhibitor indomethacin (5 mg/kg) in trachea (78%) and sem inal vesicle (64%), the serotonin and H-1 antagonist 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 vesi cle (81, 78%) and in stomach only UR-12460 (52%), whereas all of them were ineffective in thymus. When extravasation was induced by PAF (4 m u g/kg) a low dose (0.1 mg/kg) of the three PAF antagonists strongly r educed extravasation in thymus and seminal vesicle, whereas exipafant and UR-12460 did so in trachea (82, 100%) and only lexipafant in stoma ch (100%). Mepyramine, cyproheptadine, HOE-140 and indomethacin did no t inhibit the effect of PAF, whereas phenidone inhibited it br 58% in trachea. These results suggest that most of the LPS-induced increase i n vascular permeability is mediated by secondary vasoactive mediators among which PAF plays a pivotal role, although their relative contribu tion may vary from tissue to tissue. (C) 1997 Elsevier Science B.V.