Inhibition of nitric oxide synthase attenuates primed microvascular permeability in the in vivo microcirculation.
OBJECTIVE
Changes in microvascular permeability play a critical role in the inflammatory sequence of tissue injury leading to leakage of proteins and subsequent edema. Primed responses induced by topical applications of platelet-activating factor (PAF) and histamine greatly increase microvascular permeability and mimic inflammation. We assessed the role of nitric oxide (NO) by use of 1-NG-monomethyl arginine (1-NMMA, a NO synthase inhibitor), on the primed microvascular permeability. We also explored the role of mast cells and a leukocyte adhesion complex by use of cromolyn sodium and 1B6 (a monoclonal antibody), respectively.


METHODS
Forty anesthetized hamsters were separated into five groups: group 1 (n = 5) received no intervention; group 2 (n = 5) received topical 10(-9) mol/L PAF and 10(-6) mol/L histamine at a 5-minute interval; 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) received cromolyn sodium plus PAF/histamine; group 5 (n = 5) received 1B6 plus PAF/histamine. We examined the cheek pouch with intravital videomicroscopy under fluorescent epiillumination. We quantified microvascular 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 group was 8.7 +/- 5.2, whereas the group primed with PAF and histamine was 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 values 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 histamine.


CONCLUSIONS
Inhibition of NO synthase attenuates primed macromolecular extravasation in vivo. Our results indicate that NO is involved in the primed reaction of PAF and histamine, causing increases in microvascular permeability. Our study suggests a role for NO in the microcirculatory changes observed in ischemia-reperfusion injury and shock.
UMDNJ-New Jersey Medical School, Department of Surgery, Newark 07103-2714, USA.
A A
AA
Noel
S R
SR
Fallek
R W
RW
Hobson
W N
WN
Durán
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002610:Cheek; D006224:Cricetinae; D004205:Cromolyn Sodium / Q000494:pharmacology; D003911:Dextrans; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D006632:Histamine / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D016177:Macrophage-1 Antigen / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000502:physiology; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018715:Microscopy, Video; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010972:Platelet Activating Factor / Q000494:pharmacology; D019323:omega-N-Methylarginine
D003911:Dextrans; D004791:Enzyme Inhibitors; D016177:Macrophage-1 Antigen; D010972:Platelet Activating Factor; C015219:fluorescein isothiocyanate dextran; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D006632:Histamine; D001120:Arginine; D019001:Nitric Oxide Synthase; D016650:Fluorescein-5-isothiocyanate; D004205:Cromolyn Sodium