1 We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic in¯ammation in rat paw skin. We compared the eect of lipoxygenase (LOX) and cyclo-oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance P (SP), and compound 48/80. 2 Intravenous (i.v.) pre-treatment with a dual COX/LOX inhibitor (RWJ 63556), a dual LOX inhibitor/cysteinyl-leukotriene (CysLt) receptor antagonist (Rev 5901), a LOX inhibitor (AA 861), a ®ve-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacrynic acid) signi®cantly inhibited (40 to 60%) the development of neurogenic oedema, but did not aect cutaneous blood¯ow. Intradermal (i.d.) injection of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating eect. 3 Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not aect neurogenic and SP-induced oedema. Surprisingly, the structurally related COX-2 inhibitors, NS 398 and nimesulide, signi®cantly reduced both neurogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP-induced oedema, respectively). 4 COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation. 5 A mast cell stabilizer, cromolyn, and a H 1 receptor antagonist, mepyramine, signi®cantly inhibited neurogenic (51% and 43%, respectively) and SP-induced oedema (67% and 63%, respectively). 6 The co-injection of LOX inhibitors and compound 48/80 did not alter the eects of compound 48/80. Conversely, ethacrynic acid had a signi®cant potentiating eect. The pharmacological pro®le of the eect of COX inhibitors on compound 48/80-induced oedema was similar to that of neurogenic and SP-induced oedema. 7 The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not aect neurogenic or SPinduced oedema. 8 Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasma extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a signi®cant role in this process.

1 Arachidonic acid (0.01 ± 1mM) induced relaxation of precontracted rings of rabbit saphenous vein, which was counteracted by contraction at concentrations higher than 1mM. Concentrations higher than 1mM were required to induce dose-dependent contraction of vena cava and thoracic aorta from the same animals. 2 Pretreatment with a TP receptor antagonist (GR32191B or SQ29548, 3mM) potentiated the relaxant e ect in the saphenous vein, revealed a vasorelaxant component in the vena cava response and did not a ect the response of the aorta. 3 Removal of the endothelium from the venous rings, caused a 10 fold rightward shift in the concentration-relaxation curves to arachidonic acid. Whether or not the endothelium was present, the arachidonic acid-induced relaxations were prevented by indomethacin (10mM) pretreatment. 4 In the saphenous vein, PGE 2 was respectively a 50 and 100 fold more potent relaxant prostaglandin than PGI 2 and PGD 2 . Pretreatment with the EP 4 receptor antagonist, AH23848B, shifted the concentration-relaxation curves of this tissue to arachidonic acid in a dose-dependent manner. 5 In the presence of 1mM arachidonic acid, venous rings produced 8 ± 10 fold more PGE 2 than did aorta whereas 6keto-PGF 1a and TXB 2 productions remained comparable. 6 Intact rings of saphenous vein relaxed in response to A23187. Pretreatment with L-NAME (100mM) or indomethacin (10mM) reduced this response by 50% whereas concomitant pretreatment totally suppressed it. After endothelium removal, the remaining relaxing response to A23187 was prevented by indomethacin but not a ected by L-NAME. 7 We conclude that stimulation of the cyclo-oxygenase pathway by arachidonic acid induced endothelium-dependent, PGE 2 /EP 4 mediated relaxation of the rabbit saphenous vein. This process might participate in the A23187-induced relaxation of the saphenous vein and account for a relaxing component in the response of the vena cava to arachidonic acid. It was not observed in thoracic aorta because of the lack of a vasodilatory receptor and/or the poorer ability of this tissue than veins to produce PGE 2 .

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