Acute microcirculatory effects of platelet-activating factor

Using the hamster cheek pouch preparation and intravital microscopy and fluorometry methods, we quantitated the dose-response effects of topically applied platelet-activating factor (PAF) on microvascular premeability, vessel diameter and leukocyte adhesion and investigated the biochemical pathways of this compound. Premeability alterations were assessed by the clearance of macromolecules. PAF increased macromolecular clearance in a dose-dependent manner with the maximum effect being obtained at 10^-7 M. Maximal vasoconstriction was induced by 10^-5 M PAF. Interestingly, PAF at 10^-9 M induced extensive adhesion of leukocytes to postcapillary endothelium, but dit not produce changes in either vessel diameter or permeability. To elucidate the biochemical pathways of PAF activity, several inhibitors of the arachidonic acid cascade and receptor blockers were employed. Dexamethasone and kadsurenone attenueated the clearance response to PAF, while indometacin, OKY-046 (a thromboxane A₂ synthase inhibitor), and chlorpheniramine did not. Indometacin and OKY-046 prevented vessel diameter changes. Our results demonstrate that (1) PAF produces a dose-related extravasation of macromolecules, (2) leukotrienes may be responsible for the increased clearance of macromolecules caused by PAF, (3) PAF-induced vasoconstriction is mediated by thromboxane, (4) PAF stimulates leukocyte adhesion in an inverse dose relationship, and (5) responses to PAF are at least partially mediated by receptor interactions.