TY - JOUR
T1 - Dihydropyridine Antagonists and Agonists of Calcium Channels Inhibit the Induction of Nitric Oxide Synthase by Endotoxin in Cultured Macrophages
AU - Szabó, Csaba
AU - Thiemermann, Christoph
AU - Vane, John R.
PY - 1993/10/29
Y1 - 1993/10/29
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.
UR - http://www.scopus.com/inward/record.url?scp=0027430290&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0027430290&partnerID=8YFLogxK
U2 - 10.1006/bbrc.1993.2323
DO - 10.1006/bbrc.1993.2323
M3 - Article
C2 - 7694580
AN - SCOPUS:0027430290
SN - 0006-291X
VL - 196
SP - 825
EP - 830
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -