PLATELET-ACTIVATING FACTOR-INDUCED MICROVASCULAR PERMEABILITY INCREASES IN THE CAT HINDLIMB

Changes in microvascular permeability induced by platelet activating f actor (PAF) were measured in the isolated, perfused cat hindlimb prepa ration, and compared to the effect produced by another inflammatory me diator, histamine. Permeability was assessed from changes in the prote in reflection coefficient, as measured from changes in hematocrit and protein concentration resulting from microvascular fluid filtration. T he findings were 1) PAF produces transient increases in permeability s imilar to histamine, but PAF is approximately 30 times as potent; 2) t he permeability changes induced by 76 nM PAF can be totally inhibited by the specific PAF receptor blocker WEB-2086, but the blocker can onl y partially inhibit 380 nM PAF, a dose that produces a maximal increas e in permeability; 3) Diphenhydramine (2 muM), an H1-receptor blocker, totally inhibits the transient permeability increase produced by 2 mu M histamine; 4) Cimetidine (2 or 20 muM), an H2 blocker, could not inh ibit this latter increase; 5) Isoproterenol (1 muM), a beta-agonist, t otally inhibited the permeability increase produced by 1 muM histamine , but 10 muM isoproterenol only partially inhibited the maximal permea bility increase produced by 10 muM histamine; 6) Isoproterenol could n ot inhibit PAF's permeability effect; and 7) PAF's effects were unchan ged by depletion of white blood cells in the perfusate. These results suggest that PAF and histamine work through different pathways to incr ease permeability, but the final step of endothelial contraction, whic h opens large interendothelial gaps, occurs in response to both mediat ors. In addition, when concentrations of these inflammatory agents are sufficient to produce maximal permeability increases, as can occur in shock situations, then the permeability increases are more sustained and resistant to receptor inhibition. (C) 1993 Wiley-Liss, Inc.