L-ARGININE AND N-G-NITRO-L-ARGININE METHYL-ESTER CAUSE MACROMOLECULE EXTRAVASATION IN THE MICROCIRCULATION OF AWAKE HAMSTERS

We investigated the effects of L-arginine and N-G-nitro-L-arginine met hyl ester (L-NAME) on macromolecule extravasation in the microcirculat ion of awake hamsters by computer-assisted image analysis of the distr ibution of FITC (fluorescein isothiocyanate)-dextran fluorescence in d orsal fold skin preparations. This analysis made it possible to simult aneously study the time course of local (skin) and general (all irriga ted organs) extravasation in 180-min experiments. Bolus injection of 3 0 or 150 mg/kg (i.v.) L-arginine induced immediate local and general m acromolecule leakage and delayed venule dilation beginning 1 h later. Injection of 20 or 100 mg/kg (i.v.) L-NAME caused rapid venule constri ction followed by local and general extravasation beginning 45-60 min later. These effects of L-arginine and L-NAME were not mimicked by the ir biologically inactive isomers, D-arginine and D-NAME. Simultaneous bolus injection of 20 mg/kg L-NAME and 150 mg/kg L-arginine caused no significant change in fluorescence distribution or venule diameter. L- arginine effects on macromolecule extravasation were mimicked by sodiu m nitroprusside (10 mu g/kg, i.v.) and by 8-bromo-cGMP (1 mg/kg, i.v.) . Sodium nitroprusside was ineffective on venule diameter. The effects of both L-arginine and sodium nitroprusside on FITC-dextran extravasa tion were prevented by simultaneous injection (10 mu g/kg, i.v.) of th e specific inhibitor of the soluble guanylate cyclase, 1H-[1,2,4]oxadi azolo[4,3-a]quinoxalin-1-one (ODQ). This dose of ODQ mimicked the effe cts of L-NAME on macromolecule extravasation and venule diameter. Take n together, these results suggest that activation or inhibition of bas al NO synthesis might induce macromolecule leakage in the microcircula tion of awake hamsters via temporally distinct cGMP-dependent mechanis ms. (C) 1998 Elsevier Science B.V.