Comparative cytoprotective effect of dihydropyridine calcium channel blockers against the toxicity of oxidized low density lipoprotein for cultured lymphoid cells.
The ability of dihydropyridine Ca2+ channel blockers (nicardipine, nimodipine and nisoldipine) to inhibit low density lipoprotein (LDL) oxidation and to prevent the cytotoxicity of oxidized LDL for lymphoid cells have been compared. The lipid peroxidation of LDL promoted either by UV radiation or by copper ions was inhibited (antioxidant effect) in a dose-dependent manner by nisoldipine (IC50 values were evaluated at around 10 microM), whereas nimodipine was less potent (IC50 around 50-100 microM) and nicardipine almost inactive. The cytotoxicity of LDL treated (by UV or by copper) in the presence of effective antioxidant concentrations of dihydropyridine Ca2+ channel blockers was less than that of unprotected oxidized LDL (i.e. LDL oxidized in the absence of any dihydropyridine Ca2+ channel blockers). The inhibition of the cytotoxic effect of LDL oxidized in the presence of dihydropyridine Ca2+ channel blockers correlated well with protection from oxidation by these compounds. Beside this indirect protective effect, dihydropyridine Ca2+ channel blockers exhibit a direct protective effect for cells against the toxicity of previously oxidized LDL. Although complete protection cannot be obtained because of the cytotoxicity of the dihydropyridine compounds per se, the IC50 values were 6 +/- 2 and 80 +/- 20 microM for nisoldipine and nimodipine, respectively. The potential relevance to the prevention of atherogenesis is discussed.
Nègre-Salvayre
A
A
Department of Biochemistry, Faculty of Medicine, University Paul Sabatier, Toulouse, France.
Fitoussi
G
G
Troly
M
M
Salvayre
R
R
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D009529:Nicardipine / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D015737:Nisoldipine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D008077:Lipoproteins, LDL; D015737:Nisoldipine; D009553:Nimodipine; D009529:Nicardipine; D009543:Nifedipine