Effect of lead acetate on nitrite production by murine brain endothelial cell cultures.
One of the mechanisms by which lead may cause a perturbation in the nervous system is the alteration of endothelial cell function. This study investigated the effect of lead acetate on constitutive and cytokine-induced production of nitrite, a marker of nitric oxide, in brain microvascular endothelial cells. Nitric oxide synthase may be a target for lead and changes in its function can result in a cascade of physiological effects seen in vivo. Concentrations of 10, 100, and 1000 nM lead acetate, in the presence or absence of 100 ng lipopolysaccharide/ml, 400 U interferon-gamma/ml and 100 U tumor necrosis factor-alpha/ml, were added to confluent cultures of brain microvascular endothelial cells. Concentrations of lead acetate as low as 10 nM decreased constitutive levels of nitrite by 50% without inhibiting the inducible levels. Addition of 1 microM lead acetate had no effect on [3H]L-leucine incorporation, lactate dehydrogenase release, or cellular morphology, indicating that the effect was selective. Increasing the concentration of extracellular calcium to 2 mM abolished the inhibitory effect of lead acetate on the constitutive production of nitrite. These studies suggest that low concentrations of lead are capable of inhibiting nitrite produced by the calcium-dependent constitutive form of nitric oxide synthase while the calcium-independent, inducible form of nitric oxide synthase is not affected. These data provide another testable hypothesis for the as yet undetermined mechanisms of lead neurotoxicity.
Blazka
M E
ME
Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Harry
G J
GJ
Luster
M I
MI
D000594:Amino Acid Oxidoreductases / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000098:blood supply*; D002122:Calcium Chloride / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism*; D009942:Organometallic Compounds / Q000633:toxicity*; D014176:Protein Biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D009573:Nitrites; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D002122:Calcium Chloride; C008261:lead acetate