INHIBITION OF NITRIC-OXIDE SYNTHASE ATTENUATES PRIMED MICROVASCULAR PERMEABILITY IN THE IN-VIVO MICROCIRCULATION

Purpose: Changes in microvascular permeability play a critical role in the inflammatory sequence of tissue injury leading to leakage of prot eins and subsequent edema. Primed responses induced by topical applica tions of platelet-activating factor (PAF) and histamine greatly increa se microvascular permeability and mimic inflammation. We assessed the role of nitric oxide (NO) by use of 1-N-G-monomethyl arginine (1-NMMA, a NO synthase inhibitor), on the primed microvascular permeability. W e also explored the role of mast cells and a leukocyte adhesion comple x by use of cromolyn sodium and 1B6 (a monoclonal antibody), respectiv ely. Methods: Forty anesthetized hamsters were separated into five gro ups: group 1 (n = 5) received no intervention; group 2 (n = 5) receive d topical 10(-9) mol/L PAF and 10(-6) mol/L histamine at a 5-minute in terval; group 3 (n = 5 at each dose) received PAF/histamine and 1-NMMA (at 10(-5) mol/L or 10(-6) mol/L); group 4 (n = 5 at each dose) recei ved cromolyn sodium plus PAF/histamine; group 5 (n = 5) received 1B6 p lus PAF/histamine. We examined the cheek pouch with intravital videomi croscopy under fluorescent epiillumination. We quantified microvascula r permeability to fluorescein isothiocyanate-dextran 150 with computer -assisted images analysis on the basis of integrated optical intensity (IOI) measurements. Results: The mean (+/- SEM) IOI of the control gr oup was 8.7 +/- 5.2, whereas the group primed with PAP and histamine w as 62.4 +/- 10.8. The 1-NMMA (10(-5) mol/L and 10(-6) mol/L) abolished the changes in microvascular permeability (p < 0.05) yielding IOI val ues of 8.0 +/- 1.6 and 10.9 +/- 2.8, respectively. Cromolyn sodium and 1B6 did not significantly attenuate the primed response to PAF and hi stamine. Conclusion: Inhibition of NO synthase attenuates primed macro molecular extravasation in vivo. Our results indicate that NO is invol ved in the primed reaction of PAF and histamine, causing increases in microvascular permeability. Our study suggests a role for NO in the mi crocirculatory changes observed in ischemia-reperfusion injury and sho ck.