ANTIOXIDANT AND CYTOPROTECTIVE ACTIVITIES OF THE CALCIUM-CHANNEL BLOCKER MIBEFRADIL

Mibefradil is a new calcium channel antagonist (CCA) that acts on both L-and T-type channels, with 10-fold selectivity for T-type channels. In this study, the structural interactions of mibefradil with cardiac membrane lipid bilayers were directly examined with small angle x-ray diffraction approaches and correlated with lipid peroxidation and bovi ne aortic endothelial cell viability assays. Electron density profiles (Angstrom vs electrons/Angstrom(3)) calculated from the diffraction d ata (37 degrees C) demonstrated that mibefradil had an equilibrium loc ation in the hydrocarbon core/headgroup region of the cardiac bilayer, 12-27 Angstrom from the center of the membrane. Mibefradil also effec ted a pronounced reduction in electron density 0-11 Angstrom from the center of the cardiac membrane concomitant with a 7.5% (3 Angstrom) de crease in membrane hydrocarbon core thickness; these changes in membra ne structure were not observed with the phenylalkylamine verapamil, a CCA with some structural similarity to mibefradil. As a result of memb rane physico-chemical interactions, mibefradil inhibited (10-500 nM) l ipid peroxide formation in liposomes enriched in polyunsaturated fatty acids. In aortic endothelial cells, mibefradil also inhibited loss of cell viability (IC50 Of 2 mu M) following acute oxy-radical generatio n by dihydroxyfumarate and Fe ADP; the order of potency was mibefradil > verapamil > diltiazem. These findings indicate that the chemical st ructure of mibefradil contributes to biophysical interactions with the cell membrane that underlie antioxidant and cytoprotective activities in models of oxidative stress. (C) 1998 ELsevier Science Inc.