Leonhardt W, Lange M
Institute and Policlinic of Clinical Metabolic Research, Technical University Dresden, Germany.
Eur J Clin Pharmacol. 1998 Oct;54(8):603-7. doi: 10.1007/s002280050521.
Mibefradil is a novel calcium channel antagonist that selectively blocks T-channels. It acts to reduce hypertension, is cardioprotective and reduces ischemic episodes. Oxidative modification of low-density lipoproteins (LDL) is well known to contribute to coronary atherosclerosis and we therefore investigated to see whether mibefradil had antioxidative action on LDL.
Human LDL were isolated by ultracentrifugation. In vitro oxidation of LDL (0.1 micromol x l(-1) protein) in the presence of various concentrations of mibefradil was initiated by 3.2 micromol x l(-1) copper ions. The kinetics of formation of conjugated dienes was followed photometrically. Malondialdehyde and lipoperoxides were determined at maximum oxidation. LDL (0.3 micromol x l(-1)) were also pre-incubated with mibefradil (120 micromol x l(-1)). Excessive mibefradil was separated by column technique. The resultant LDL were oxidized using copper ions or (AAPH) 2,2'-azobis(2-amidinopropane) hydrochloride.
The presence of mibefradil in the concentration range from 10 to 200 micromol x l(-1) had dose-dependent effects. These were protection of LDL against oxidation measured as prolongation of the lagtime up to 250%, and reduction in the formation of malondialdehyde down to 65% and of lipoperoxides to 20%. Pre-incubation of LDL with mibefradil prolonged the lagtime of Cu-mediated oxidation up to 132% and of AAPH-mediated oxidation up to 138%.
In addition to the T-channel blocking and antiproliferative effects, our results provide arguments for a protective role of mibefradil (10-200 micromol x l(-1)) on LDL against in vitro oxidation. This was shown with three independent parameters (lagtime, malondialdehyde and lipoperoxides) and in different oxidation models.
