Platelet-activating factor (PAF) antagonists produce doserelated inhbftion of leukocyte adhesion in rat mesenterc venules

Abstract

Proinflammatory mediators such as histamine promote expression of Pselectin and PAF on endothelium of post-capillary venules, events which can lead to rolling and adhesion of leukocytes to the vessel wall. Although these interactions have been modified by PAF antagonists at single dose levels, dose-response data for this phenomenon has not been reported. To address this issue, we used intravital microscopy to examine the effect of three PAF antagonists on leukocyte adhesion 50-60 mh after superfusion of rat mesentery with histamine (100 nM). Adhesion in 13 control rats was 16 +/- 4 cells/100 urn vessel length. Three additional groups of rats were treated intravenously 15 min before starting histamine with WEB-2086 (0.1 10 mg/kg, n=15), SR-27.417 (0.001 - 0.1 mg/kg, n=12) or BB-882 (0.001 - 0.1 mg/kg, n=15). Each of these structurally-unrelated PAF antagonists produced dose-related inhibition of leukocyte adhesion (ED = 1.8, 0.002 and 0.003 mg/kg for WEB-2086, SR-27,417 and BB-882, respectively). Inhibition of PAF binding to rabbit platelet membranes exhibited a rank order of potency (K, = 98, 1.1 and 0.4 nM for the respective agents) which was similar to the potency order for inhibiting adhesion in our experiments. In addition, the ability of SR-27,417 and BB-882 to block the increase in rat skin permeability induced by intravenous PAF injection (EDM = 0.01 and 0.02 mg/kg) was comparable to the in vitro potencies and to the results on cell adhesion. These findings support a role for endothelial-derived PAF in the activation and subsequent adhesion of leukocytes induced by histamine, and the efficacy of PAF antagonists in ameliorating this process.