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.
Mason
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Department of Biochemistry, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Pittsburgh, PA 15212-4772, USA. mason@pgh.auhs.edu
Mak
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Walter
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Tulenko
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Mason
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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