HISTAMINE-INDUCED BIPHASIC MACROMOLECULAR LEAKAGE IN THE MICROCIRCULATION OF THE CONSCIOUS HAMSTER - EVIDENCE FOR A DELAYED NITRIC-OXIDE DEPENDENT LEAKAGE

1 Late effects (up to 3 h) of intravenously-injected histamine on FITC -dextran extravasation were investigated in the conscious hamster, by use of computer-assisted image analysis of fluorescence distribution i n a microscopic window of dorsal skin fold preparations. This analysis allowed measurement of local (skin) and general (all organs) extravas ations caused by a bolus injection of histamine (1 mg kg(-1), i.v.) 2 Histamine doses higher than 0.01 mg kg(-1) caused biphasic local and g eneral extravasations. Initial phases developed fully within 15 min (f or local) and 60 min (for general) and were followed by late phases be ginning 90 min after histamine injection. Although the initial and lat e phases of histamine-induced extravasations had differential apparent reactivities to the autacoid, all the effects of histamine on the mic rocirculation (1 mg kg(-1)) were inhibited by pyrilamine (1 mg kg(-1), i.v.) but not by cimetidine (1 mg kg(-1), i.v.). 3 Pretreatment with N-G-monomethyl-L-arginine (L-NMMA, 30 mg kg(-1), i.v.) or N-G-nitro-L- arginine methyl ester (L-NAME, 100 mg kg(-1), i.v.) did not affect the initial phases but did prevent the late phases of local and general e xtravasations triggered by 1 mg kg(-1) histamine. The inhibitory effec ts oft-NAME were reversed by L-arginine (30 mg kg(-1)) but not by D-ar ginine (30 mg kg(-1)) according to the enantioselectivity of nitric ox ide synthase (NOS). A late NO-mediated venular dilatation occurred in response to plasma histamine. 4 A low dose of aminoguanidine (1 mg kg( -1), i.v.), a selective inhibitor of the inducible isoform of NOS (iNO S), mimicked the inhibitory effects of L-NAME on the late phases of hi stamine-induced macromolecular extravasations and venular dilatation. 5 Pretreatment with dexamethasone (1 mg kg(-1), i.v.) prevented both t he initial and late phases of histamine-induced extravasations. Fucoid an (1 or 25 mg kg(-1), i.v.) prevented the late phases without affecti ng initial phases, consistent with a role for leukocytes adhesion in t he development of the late NO-mediated effects of histamine. 6 We conc lude that intravenous injection of histamine triggers a biphasic infla mmatory cascade via initial activation of H-1 receptors which induces a late NO-mediated PMN-dependent extravasation process.