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 bovine aortic endothelial cell viability assays. Electron density profiles (A vs electrons/A3) calculated from the diffraction data (37 degrees C) demonstrated that mibefradil had an equilibrium location in the hydrocarbon core/headgroup region of the cardiac bilayer, 12-27 A from the center of the membrane. Mibefradil also effected a pronounced reduction in electron density 0-11 A from the center of the cardiac membrane concomitant with a 7.5% (3 A) 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 (IC50 of 2 microM) 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.
Department of Biochemistry, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Pittsburgh, PA 15212-4772, USA. mason@pgh.auhs.edu
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D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D017665:Hydroxyl Radical / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D020748:Mibefradil; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*; D014700:Verapamil / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014961:X-Ray Diffraction
D000975:Antioxidants; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D008051:Lipid Bilayers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D017665:Hydroxyl Radical; D014700:Verapamil