Cheng H Y, Randall C S, Holl W W, Constantinides P P, Yue T L, Feuerstein G Z
SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Biochim Biophys Acta. 1996 Oct 2;1284(1):20-8. doi: 10.1016/0005-2736(96)00097-1.
Carvedilol (Kredex, Coreg) is a multiple action antihypertensive drug that has been shown to protect cell membranes from lipid peroxidative damages. In this study the physical and structural effects of carvedilol on lipid bilayers are investigated by fluorescence techniques, differential scanning calorimetry and other physical methods. Carvedilol binds to liposomal membranes (9:1 DMPC:DMPG) strongly with an apparent binding constant on the order of 10(4) M-1 in PBS (pH 7.4). The characteristic changes in its intrinsic fluorescence properties when bound to liposomes suggest that this compound is situated in a non-polar environment. The Stern-Volmer and bimolecular quenching constants, determined using nitrate as the fluorescence quencher, for the free and bound carvedilol indicate that the carbazole moiety is at a depth of > 11 A in the lipid bilayer. Fluorescence anisotropy measurements show that, unlike the membrane probes DPH and TMA-DPH, carvedilol is relatively mobile, and does not have a rigidly-defined molecular orientation in the bilayers. Differential scanning calorimetry results indicate that carvedilol is an effective membrane "fluidizer' as it dose-dependently lowers the gel to liquid crystalline transition temperature and broadens the endothermic transition. Comparative studies of interactions of carbazole, 4-OH carbazole and carvedilol with the model liposomal membranes reveal a possible role of membrane-partitioning in their antioxidant efficacy. These findings are discussed in perspective with the membrane biophysical properties of different classes of therapeutic significant lipid antioxidants in mind.
卡维地洛（Kredex，Coreg）是一种具有多种作用的抗高血压药物，已被证明可保护细胞膜免受脂质过氧化损伤。在本研究中，通过荧光技术、差示扫描量热法和其他物理方法研究了卡维地洛对脂质双层的物理和结构影响。卡维地洛与脂质体膜（9:1二肉豆蔻酰磷脂酰胆碱：二肉豆蔻酰磷脂酰甘油）强烈结合，在磷酸盐缓冲液（pH 7.4）中的表观结合常数约为10⁴ M⁻¹。其与脂质体结合时固有荧光特性的特征变化表明该化合物位于非极性环境中。使用硝酸盐作为荧光猝灭剂测定的游离和结合卡维地洛的斯特恩-沃尔默和双分子猝灭常数表明，咔唑部分在脂质双层中的深度大于11 Å。荧光各向异性测量表明，与膜探针DPH和TMA-DPH不同，卡维地洛相对可移动，并且在双层中没有严格定义的分子取向。差示扫描量热法结果表明，卡维地洛是一种有效的膜“流化剂”，因为它剂量依赖性地降低凝胶到液晶的转变温度并拓宽吸热转变。咔唑、4-羟基咔唑和卡维地洛与模型脂质体膜相互作用的比较研究揭示了膜分配在其抗氧化功效中的可能作用。考虑到不同类别的具有治疗意义的脂质抗氧化剂的膜生物物理特性，对这些发现进行了讨论。
