Respective role of lipoxygenase and nitric oxide synthase pathways in plasma histamine-induced macromolecular leakage in conscious hamsters

1 Intravital microscopy technique was used to determine the distribution of a fluorescent plasma marker (fluorescein-isothiocyanate-dextran, 150 kD; F D-150) into venular and interstitial compartments of dorsal skin fold prepa rations in conscious hamsters. 2 One mg kg(-1) histamine (i.v.) caused a biphasic decrease in venular fluo rescence due to FD-150 extravasation in all organs (general extravasation). Immediately after injection, the venular fluorescence decreased and platea ued in 60 min. Ninety minutes after histamine injection, venular fluorescen ce further decreased until 180 min. Prior treatment with indomethacin (0.1 mg kg(-1), i.v.) did not modify the time-course of general extravasation bu t prevented histamine-induced venule dilatation. 3 Prior treatment with the 5-lipoxygenase activating protein (FLAP) inhibit or, 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimeth yl-propanoic acid sodium (MK-886)(10 mu g kg(-1), i.v.), the leukotriene re ceptor antagonist, benzenemethanol a-pentyl-3-(2-quinolinylmethoxy) (REV-59 01)(1 mg kg(-1) i.v.), or the glutathione-S-transferase inhibitor, ethacryn ic acid (1 mg kg(-1), i.v.), delayed by 60 min the onset of general extrava sation caused by 1 mg kg(-1) histamine. 4 Prior treatment with lipoxygenase pathway inhibitors and N-G-nitro-L-argi nine-methylester (L-NAME)(100 mg kg(-1), i.v.) abolished the general extrav asation and venule dilatation induced by 1 mg kg(-1) histamine. 5 Injection of 1 mu g kg(-1) (i.v.), of leukotriene-C-4 (LTC4) or -D-4 (LTD 4) induced immediate and sustained general extravasation and reduction in v enule diameter, these effects being blocked by REV-5901. 6 Histamine (1 mg kg(-1), i.v.) induced biphasic decline in mean arterial b lood pressure (MAP). An initial phase (from 0 to 60 min) was followed by a late phase beginning 90 min after histamine injection. L-NAME (100 mg kg(-1 ), i.v.) and aminoguanidine (1 mg kg(-1), i.v.) prevented the late phase of histamine-induced hypotension. 7 Thus, plasma histamine can trigger both an immediate cysteinyl-leukotrien e (Cys-LT)-dependent and a late nitric oxide (NO)-mediated inflammatory cas cade. Although the cyclo-oxygenase (COX) pathway might account for histamin e-induced venule dilatation, it would not influence histamine-induced extra vasation.