Platelet activating factor-induced microvascular permeability increases in the cat hindlimb.
Changes in microvascular permeability induced by platelet activating factor (PAF) were measured in the isolated, perfused cat hindlimb preparation, and compared to the effect produced by another inflammatory mediator, histamine. Permeability was assessed from changes in the protein reflection coefficient, as measured from changes in hematocrit and protein concentration resulting from microvascular fluid filtration. The findings were 1) PAF produces transient increases in permeability similar to histamine, but PAF is approximately 30 times as potent; 2) the permeability changes induced by 76 nM PAF can be totally inhibited by the specific PAF receptor blocker WEB-2086, but the blocker can only partially inhibit 380 nM PAF, a dose that produces a maximal increase in permeability; 3) Diphenhydramine (2 microM), an H1-receptor blocker, totally inhibits the transient permeability increase produced by 2 microM histamine; 4) Cimetidine (2 or 20 microM), an H2 blocker, could not inhibit this latter increase; 5) Isoproterenol (1 microM), a beta-agonist, totally inhibited the permeability increase produced by 1 microM histamine, but 10 microM isoproterenol only partially inhibited the maximal permeability increase produced by 10 microM histamine; 6) Isoproterenol could not inhibit PAF's permeability effect; and 7) PAF's effects were unchanged by depletion of white blood cells in the perfusate. These results suggest that PAF and histamine work through different pathways to increase permeability, but the final step of endothelial contraction, which opens large inter-endothelial gaps, occurs in response to both mediators. 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.
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Department of Physiology, University of South Carolina School of Medicine, Columbia 29208.
Wolf
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D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002415:Cats; D002927:Cimetidine / Q000494:pharmacology; D004155:Diphenhydramine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply*; D006632:Histamine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007958:Leukocyte Count; D007962:Leukocytes / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D002927:Cimetidine; D006632:Histamine; D004155:Diphenhydramine; D007545:Isoproterenol