Mason R P, Walter M F, Trumbore M W, Olmstead E G, Mason P E
Department of Biochemistry, Cardiovascular and Pulmonary Research Institute, MCP-Hahnemann School of Medicine, Allegheny University of Health Sciences, Pittsburgh, PA 15212-4772, USA.
J Mol Cell Cardiol. 1999 Jan;31(1):275-81. doi: 10.1006/jmcc.1998.0867.
The effect of the highly lipophilic calcium channel antagonist (CCA) amlodipine on membrane oxyradical damage was examined and compared to that of other CCA analogs and a sulfhydryl-containing ACE inhibitor in isolated membrane vesicles enriched with polyunsaturated fatty acids (PUFA). Under physiological-like conditions, the dihydropyridine CCA amlodipine significantly (P<0.001) inhibited lipid peroxide formation (>10(2) microM) at concentrations as low as 10.0 nM. Under identical conditions, inhibition of lipid peroxide formation was not observed with representative CCA analogs (felodipine, verapamil, diltiazem) or the ACE inhibitor, captopril, at concentrations as high as 1.0 microM. The potent antioxidant activity of amlodipine is attributed to distinct membrane physico-chemical interactions. High-resolution differential scanning calorimetry showed that amlodipine effected marked changes in membrane thermodynamic properties as compared to other CCA analogs, including a marked reduction in the thermal phase transition temperature (-2.6 degrees C), enthalpy (-4.8 J/g) and cooperative unit size (-59%), relative to control samples. These findings indicate that the chemical structure of amlodipine contributes to distinct membrane biophysical interactions that lead to potent lipid antioxidant effects, independent of calcium channel modulation. These findings provide insights into potential new mechanisms of action for the charged CCA amlodipine.
研究了高亲脂性钙通道拮抗剂（CCA）氨氯地平对膜氧自由基损伤的影响，并将其与其他CCA类似物以及一种含巯基的血管紧张素转换酶抑制剂（ACE抑制剂）在富含多不饱和脂肪酸（PUFA）的分离膜囊泡中的作用进行了比较。在类似生理条件下，二氢吡啶类CCA氨氯地平在低至10.0 nM的浓度下就能显著（P<0.001）抑制脂质过氧化物的形成（>10²μM）。在相同条件下，代表性的CCA类似物（非洛地平、维拉帕米、地尔硫䓬）或ACE抑制剂卡托普利在高达1.0 μM的浓度下未观察到脂质过氧化物形成的抑制作用。氨氯地平的强抗氧化活性归因于独特的膜物理化学相互作用。高分辨率差示扫描量热法表明，与其他CCA类似物相比，氨氯地平使膜的热力学性质发生了显著变化，相对于对照样品，热相变温度显著降低（-2.6℃）、焓（-4.8 J/g）和协同单元大小（-59%）。这些发现表明，氨氯地平的化学结构有助于形成独特的膜生物物理相互作用，从而产生强大的脂质抗氧化作用，这与钙通道调节无关。这些发现为带电荷的CCA氨氯地平潜在的新作用机制提供了见解。
