NEUROGENIC AND NON-NEUROGENIC MECHANISMS OF PLASMA EXTRAVASATION IN THE RAT

We describe two distinct mechanisms for the enhancement of plasma extravasation in the knee joint of the rat. One is activated by bradykinin and is neurogenic; the other is activated by platelet-activating factor and is non-neurogenic. Bradykinin-induced synovial plasma extravasation is known to be dependent on the sympathetic postganglionic neuron terminal, and to involve prostaglandins, ATP, adenosine A2 receptor action, and the attraction and activation of neutrophils. In this study we found that bradykinin-induced plasma extravasation also involves endothelium-derived relaxing factor; specifically we found that bradykinin-induced plasma extravasation was antagonized stereospecifically by the inhibitor of endothelium-derived relaxing factor synthesis, N(G)-monomethyl-L-arginine. Perfused alone, platelet-activating factor produced an increase in synovial plasma extravasation which was markedly reduced by the platelet-activating factor receptor antagonists BN 52021 and WEB 2086 (these antagonists did not affect bradykinin-induced plasma extravasation). Platelet-activating factor-induced plasma extravasation was not affected by N(G)-monomethyl-L-arginine, indomethacin (a prostaglandin synthesis inhibitor), phenol 3-(5H-thiozolo[2,3b]quinazolin) (an A2 receptor adenosine antagonist), dextran sulfate (an inhibitor of leukocyte rolling), hydroxyurea (a depletor of leukocytes), chronic sympathectomy or the depletion of unmyelinated afferent fibers. Of note, the magnitude of platelet-activating factor-induced plasma extravasation was increased by co-perfusion with prostaglandin E2 and attenuated by co-perfusion with L-arginine; that is, two of the mediators involved in neurogenic bradykinin-induced plasma extravasation exerted an influence on non-neurogenic plasma extravasation. Separate mechanisms for bradykinin and platelet-activating factor plasma extravasation were further demonstrated in the streptozotocin-treated diabetic rat, in which there is a peripheral neuropathy. Neurogenic, bradykinin-induced plasma extravasation was greatly decreased in diabetic animals while non-neurogenic, platelet-activating factor-induced plasma extravasation was unchanged.