Mason R P, Trumbore M W
Department of Psychiatry, Medical College of Pennsylvania, Pittsburgh 15212-4772, USA.
Biochem Pharmacol. 1996 Mar 8;51(5):653-60. doi: 10.1016/s0006-2952(95)02238-4.
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.
脂质过氧化在衰老及包括动脉粥样硬化在内的各种疾病过程中会导致细胞损伤。长期给予高度亲脂性钙通道阻滞剂（CCB）可能会由于其在细胞膜中的聚集以及改变脂质双层的物理化学性质而减少脂质过氧化。在该研究中，小角X射线散射被用于检测在具有不同抗氧化活性的CCB（包括尼索地平、硝苯地平和地尔硫䓬）存在的情况下重构的心脏膜脂质双层。对一维电子密度分布的分析表明，这些化合物相对于膜中心具有不同的分子分布：地尔硫䓬（±14 - 22 Å）、硝苯地平（±12 - 22 Å）和尼索地平（±7 - 22 Å）。对照样品的总体烃核宽度为44 Å，在这些浓度（质量分数<1%）下添加药物并未对其产生影响。高分辨率差示扫描量热法表明，相对于对照样品，CCB显著扰乱了脂质体的热致性质，包括热相变温度和焓。这些化合物对膜热致性质的影响与其所报道的抗氧化活性相关。这些数据支持了钙通道阻滞剂与膜脂质双层具有强大的物理化学相互作用这一假说，这可能是其抗氧化活性的基础。
