Microvascular responses to inhibition of nitric oxide production. Role of active oxidants.
The objective of this study was to assess the potential contribution of hydrogen peroxide (H2O2) to the leukocyte-endothelial cell adhesion and increased microvascular permeability observed in rat mesenteric venules after inhibition of nitric oxide synthesis with NG-nitro-L-arginine methyl ester (L-NAME). Leukocyte adherence and emigration and leakage of fluorescein isothiocyanate-labeled albumin were monitored in postcapillary venules before and after exposure of the tissue to L-NAME. H2O2 production in mesenteric tissue was monitored by using dihydrorhodamine 123 (DHR), the H2O2-sensitive fluorochrome. L-NAME elicited a rapid increase in both the rate of albumin extravasation and oxidation of DHR, which was followed by an increased adherence and emigration of leukocytes in postcapillary venules. Treatment with either catalase or dimethylthiourea attenuated the L-NAME-induced oxidative stress, albumin leakage, and leukocyte-endothelial cell adhesion. Oxidation of DHR was enhanced in animals treated with either 3-amino-1,2,4-triazole (ATZ), an inhibitor of endogenous catalase, or a combination of ATZ and maleic acid diethyl ester, which depletes intracellular glutathione. Animals receiving a CD11/CD18-specific antibody to prevent leukocyte adhesion/emigration exhibited a reduced oxidation of DHR in response to L-NAME. These findings indicate that most of the H2O2 (and secondarily derived oxidants) generated in mesenteric tissue exposed to an inhibitor of nitric oxide production is due to accumulation of activated leukocytes.
Kurose
I
I
Department of Physiology, LSU Medical Center, Shreveport 71130-3932.
Wolf
R
R
Grisham
M B
MB
Aw
T Y
TY
Specian
R D
RD
Granger
D N
DN
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018821:CD18 Antigens / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012235:Rhodamines / Q000378:metabolism; D014699:Venules / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D018821:CD18 Antigens; D012235:Rhodamines; C058319:dihydrorhodamine 123; D009569:Nitric Oxide; D001120:Arginine; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester; D000640:Amitrole