Dihydropyridine Antagonists and Agonists of Calcium Channels Inhibit the Induction of Nitric Oxide Synthase by Endotoxin in Cultured Macrophages

Csaba Szabo, C. Thiemermann, J. R. Vane

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Abstract

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 - 3×10-6 M for 30 min) dose-dependently inhibited the LPS-stimulated (1 μg/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 4h 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, dihydropyridi ne 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.

Original languageEnglish (US)
Pages (from-to)825-830
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume196
Issue number2
DOIs
StatePublished - Oct 29 1993
Externally publishedYes

Fingerprint

Calcium Channel Agonists
Macrophages
Calcium Channel Blockers
Nitrites
Nitrendipine
Endotoxins
Nitric Oxide Synthase
Nimodipine
Nisoldipine
Calcium Channels
Modulators
Dihydropyridines
Calcium
Lipopolysaccharides
Protein Isoforms
Respiration
Modulation
1,4-dihydropyridine

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry

Cite this

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title = "Dihydropyridine Antagonists and Agonists of Calcium Channels Inhibit the Induction of Nitric Oxide Synthase by Endotoxin in Cultured Macrophages",
abstract = "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 - 3×10-6 M for 30 min) dose-dependently inhibited the LPS-stimulated (1 μg/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 4h 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, dihydropyridi ne 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.",
author = "Csaba Szabo and C. Thiemermann and Vane, {J. R.}",
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T1 - Dihydropyridine Antagonists and Agonists of Calcium Channels Inhibit the Induction of Nitric Oxide Synthase by Endotoxin in Cultured Macrophages

AU - Szabo, Csaba

AU - Thiemermann, C.

AU - Vane, J. R.

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N2 - 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 - 3×10-6 M for 30 min) dose-dependently inhibited the LPS-stimulated (1 μg/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 4h 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, dihydropyridi ne 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.

AB - 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 - 3×10-6 M for 30 min) dose-dependently inhibited the LPS-stimulated (1 μg/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 4h 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, dihydropyridi ne 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.

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