Nitric oxide inhibits microvascular protein leakage induced by leukocyte adhesion-independent and adhesion-dependent inflammatory mediators.
OBJECTIVE
The purpose of this study was to determine whether exogenous nitric oxide could block permeability alterations induced by neutrophil-independent (histamine) and neutrophil-dependent (CINC/gro) inflammatory mediators.


METHODS
Intravital microscopy was used in the rat mesentery to examine leukocyte adhesion, transvascular FITC-albumin leakage, and perivascular mast cell activation (ruthenium red uptake) in response to local superfusion with histamine or the chemokine CINC/gro. The effects of the nitric oxide donor spermine-NO, or the cGMP analog 8-Br-cGMP were examined.


RESULTS
Histamine superfusion increased vascular protein leakage within minutes, but did not increase firm adhesion above that seen in control preparations. The increase in albumin leakage could be prevented by co-administration of spermine-NO, but was not affected by 8-Br-cGMP. CINC/gro elicited a linear increase in vascular protein leakage and a profound increase in leukocyte adhesion. Treatment with spermine-NO or 8-Br-cGMP significantly attenuated increases in both adhesion and albumin leakage. The actions of spermine-NO and 8-Br-cGMP were not due to mast cell stabilization as neither histamine nor CINC/gro elicited mast cell activation.


CONCLUSIONS
This study demonstrates that exogenous nitric oxide and 8-Br-cGMP could block adhesion dependent alterations in vascular permeability induced by CINC/gro, while adhesion-independent alterations in permeability induced by histamine could be blocked by exogenous NO but not 8-Br-cGMP. This suggests that different NO-dependent signalling pathways are important in modulating these two types of vascular protein leakage.
Johnston
B
B
Department of Physiology and Biophysics, University of Calgary, Alberta, Canada.
Gaboury
J P
JP
Suematsu
M
M
Kubes
P
P
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000494:pharmacology; D002630:Chemotactic Factors / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D009589:Nitrogen Oxides; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D006133:Growth Substances; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D009589:Nitrogen Oxides; D011506:Proteins; C091861:spermine nitric oxide complex; D013096:Spermine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D006632:Histamine; D006152:Cyclic GMP