Dihydropyridine antagonists and agonists of calcium channels inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages.
Here we investigate the effects of the dihydropyridine-type antagonists of calcium channels nitrendipine, nimodipine, nisoldipine and the calcium channel agonist BAY K 8644 on the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in J774.2 macrophages cultured in vitro. Pretreatment of J774.2 cells with these dihydropyridines (10(-8) -3 x 10(-6) M for 30 min) dose-dependently inhibited the LPS-stimulated (1 microgram/ml, 24 h) nitrite formation. For instance, at 10(-6) M, the inhibition was 59 +/- 3% for nitrendipine; 47 +/- 5% for nimodipine and 42 +/- 3% for nisoldipine (n = 9; p < 0.05). BAY K 8644 caused a moderate, but significant inhibition of nitrite accumulation (by 16 +/- 3% at 10(-7) M, n = 9; p < 0.05). The inhibition of LPS-stimulated nitrite accumulation produced by nitrendipine, nimodipine, and BAY K 8644 was significantly smaller when they were applied 2 or 4 h after LPS, indicating that these agents inhibit the induction, but not the activity of the induced NOS. At concentrations which caused a significant inhibition of the LPS-stimulated nitrite accumulation, the dihydropyridine calcium channel modulators did not inhibit mitochondrial respiration. Thus, dihydropyridine calcium channel modulators (antagonists and an agonist) inhibit the induction of the calcium-independent isoform of NOS produced by LPS in J774.2 macrophages. This effect is not related to the modulation of intracellular calcium levels.
Szabó
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William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Thiemermann
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C
Vane
J R
JR
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D004731:Endotoxins / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004926:Escherichia coli; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D009553:Nimodipine / Q000494:pharmacology; D015737:Nisoldipine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D019001:Nitric Oxide Synthase
D002121:Calcium Channel Blockers; D004731:Endotoxins; D008070:Lipopolysaccharides; D015737:Nisoldipine; D009553:Nimodipine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009568:Nitrendipine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases