Antioxidant and Cytoprotective Activities of the Calcium Channel Blocker Mibefradil

• Published in: Biochemical pharmacology Vol. 55; no. 11; pp. 1843 - 1852
• Main Authors: Mason, R.Preston, Mak, I.Tong, Walter, Mary F, Tulenko, Thomas N, Mason, Pamela E
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.1998; Elsevier Science
• Subjects: Animals; Antiarythmic agents; Antioxidants - chemistry; Antioxidants - pharmacology; Aorta - cytology; Aorta - drug effects; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; calcium channel antagonists; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Cardiovascular system; Cattle; Cell Survival - drug effects; Cells, Cultured; endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Hydroxyl Radical - metabolism; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; lipid peroxidation; Lipid Peroxidation - drug effects; Medical sciences; Mibefradil; Myocardium - metabolism; Oxidation-Reduction; Pharmacology. Drug treatments; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - pharmacology; Verapamil - chemistry; Verapamil - metabolism; Verapamil - pharmacology; X-Ray Diffraction; endothelial cells; x-ray diffraction; calcium channel antagonists; lipid peroxidation; Endothelial cell; Mibefradil; Cytoprotector; Pharmacological activity; Calcium antagonist; Plasma membrane; Lipids; Antioxidant; In vitro; Biological activity; Peroxidation
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(98)00070-7

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 bovine aortic endothelial cell viability assays. Electron density profiles (Å vs electrons/Å 3) calculated from the diffraction data (37°C) demonstrated that mibefradil had an equilibrium location in the hydrocarbon core/headgroup region of the cardiac bilayer, 12–27Å from the center of the membrane. Mibefradil also effected a pronounced reduction in electron density 0–11Å from the center of the cardiac membrane concomitant with a 7.5% (3Å) decrease in membrane hydrocarbon core thickness; these changes in membrane structure were not observed with the phenylalkylamine verapamil, a CCA with some structural similarity to mibefradil. As a result of membrane physico-chemical interactions, mibefradil inhibited (10–500 nM) lipid peroxide formation in liposomes enriched in polyunsaturated fatty acids. In aortic endothelial cells, mibefradil also inhibited loss of cell viability ( ic 50 of 2 μM) following acute oxy-radical generation by dihydroxyfumarate and Fe-ADP; the order of potency was mibefradil > verapamil > diltiazem. These findings indicate that the chemical structure of mibefradil contributes to biophysical interactions with the cell membrane that underlie antioxidant and cytoprotective activities in models of oxidative stress.