The effects of calcium channel blockers on nuclear factor kappa B activation in the mesangium cells.
It has been reported that calcium channel blockers (CCBs) have an inhibitory action on cell growth and transcriptional changes induced by cytokines and hormones. In this study, we examined the effects of CCBs on nuclear factor kappa B (NFkappaB), which plays a key role in the intracellular signaling of various growth factors and cytokines. The activity of NFkappaB was determined by luciferase assay with the transfection of the reporter gene, which has six NFkappaB-recognizing sequences in the upstream of herpes simplex virus thymidine kinase promoter. In cultured human mesangial cells, increased intracellular calcium concentration by calcium ionophore, A23187, showed a stimulatory effect on the phorbor 12-myristate 13-acetate (PMA)-induced activation of NFkappaB, while L-type calcium channel agonist, Bay K 8644, did not have any significant effects on either basal or PMA-stimulated activity of NFkappaB. At a higher concentration (10 microM), nifedipine, verapamil, or efonidipine showed an inhibitory effect on the activation of NFkappaB by PMA and A23187, while at a lower concentration (1 microM), only efonidipine showed a significant inhibitory effect. From these results, we conclude that CCBs have an inhibitory effect on NFkappaB via the independent pathway of an L-type calcium channel and that the potency of this effect is variable among L-type calcium channel blockers.
Hayashi
M
M
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Yamaji
Y
Y
Nakazato
Y
Y
Saruta
T
T
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D009596:Nitrophenols; D009943:Organophosphorus Compounds / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002273:Carcinogens; D004095:Dihydropyridines; D007476:Ionophores; D016328:NF-kappa B; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D000001:Calcimycin; C066425:efonidipine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D008156:Luciferases; D009543:Nifedipine; D013755:Tetradecanoylphorbol Acetate