Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, China.
Acta Pharmacol Sin. 2011 Feb;32(2):141-51. doi: 10.1038/aps.2010.197.
The positive inotropic effect of cardiac glycosides lies in their reversible inhibition on the membrane-bound Na(+)/K(+)-ATPase in human myocardium. Steroid-like compounds containing a core structure similar to cardiac glycosides are found in many Chinese medicines conventionally used for promoting blood circulation. Some of them are demonstrated to be Na(+)/K(+)-ATPase inhibitors and thus putatively responsible for their therapeutic effects via the same molecular mechanism as cardiac glycosides. On the other hand, magnesium lithospermate B of danshen is also proposed to exert its cardiac therapeutic effect by effectively inhibiting Na(+)/K(+)-ATPase. Theoretical modeling suggests that the number of hydrogen bonds and the strength of hydrophobic interaction between the effective ingredients of various medicines and residues around the binding pocket of Na(+)/K(+)-ATPase are crucial for the inhibitory potency of these active ingredients. Ginsenosides, the active ingredients in ginseng and sanqi, substantially inhibit Na(+)/K(+)-ATPase when sugar moieties are attached only to the C-3 position of their steroid-like structure, equivalent to the sugar position in cardiac glycosides. Their inhibitory potency is abolished, however, when sugar moieties are linked to C-6 or C-20 position of the steroid nucleus; presumably, these sugar attachments lead to steric hindrance for the entrance of ginsenosides into the binding pocket of Na(+)/K(+)-ATPase. Neuroprotective effects of cardiac glycosides, several steroid-like compounds, and magnesium lithospermate B against ischemic stroke have been accordingly observed in a cortical brain slice-based assay model, and cumulative data support that effective inhibitors of Na(+)/K(+)-ATPase in the brain could be potential drugs for the treatment of ischemic stroke.
强心苷的正性肌力作用在于其对人心肌细胞膜结合的 Na(+)/K(+)-ATP 酶的可逆抑制。许多传统用于促进血液循环的中药中都含有与强心苷相似的甾体样化合物。其中一些被证明是 Na(+)/K(+)-ATP 酶抑制剂，因此通过与强心苷相同的分子机制，它们可能对其治疗作用负责。另一方面，丹参中的镁 Lithospermate B 也被认为通过有效抑制 Na(+)/K(+)-ATP 酶发挥其心脏治疗作用。理论建模表明，各种药物的有效成分与 Na(+)/K(+)-ATP 酶结合口袋周围残基之间氢键的数量和疏水力的强度对于这些活性成分的抑制效力至关重要。人参和三七中的有效成分人参皂苷，当糖基仅连接到其甾体样结构的 C-3 位时，会显著抑制 Na(+)/K(+)-ATP 酶，与强心苷中的糖基位置相当。然而，当糖基连接到甾体核的 C-6 或 C-20 位时，它们的抑制效力就会被废除；推测这些糖基的连接会阻碍人参皂苷进入 Na(+)/K(+)-ATP 酶的结合口袋。在皮质脑片测定模型中观察到强心苷、几种甾体样化合物和镁 Lithospermate B 对缺血性中风的神经保护作用，累积数据支持脑内有效的 Na(+)/K(+)-ATP 酶抑制剂可能是治疗缺血性中风的潜在药物。
