Differential membrane interactions of calcium channel blockers. Implications for antioxidant activity.

Lipid peroxidation causes cellular damage during aging and various diseases, including atherosclerosis. Chronic administration of highly lipophilic calcium channel blockers (CCB) may reduce lipid peroxidation as a result of concentration in cell membranes and altering physico-chemical properties of the lipid bilayer. In the study, small angle X-ray scattering was used to examine reconstituted cardiac membrane lipid bilayers in the presence of CCB with various antioxidant activities, including nisoldipine, nifedipine, and diltiazem. Analysis of one-dimensional electron density profiles demonstrated that these compounds have different molecular distributions relative to the center of the membrane: diltiazem (+/- 14-22 A), nifedipine (+/- 12-22 A), and nisoldipine (+/- 7-22 A). The overall hydrocarbon core width for control samples was 44 A and was unaffected by the addition of drugs at these concentrations (< 1% by mass). High resolution differential scanning calorimetry indicated that CCB markedly perturbed the thermotropic properties of liposomes, including thermal phase transition temperature and enthalpy, relative to control samples. The effects of these compounds on membrane thermotropic properties correlate with their reported antioxidant activities. These data support the hypothesis that calcium channel blockers have potent physico-chemical interactions with the membrane lipid bilayer, which may underlie their antioxidant activity.