Active ingredients in Chinese medicines promoting blood circulation as Na＋/K＋-ATPase inhibitors

• Published in: Acta pharmacologica Sinica Vol. 32; no. 2; pp. 141 - 151
• Main Authors: Chen, Ronald JY, Jinn, Tzyy-rong, Chen, Yi-ching, Chung, Tse-yu, Yang, Wei-hung, Tzen, Jason TC
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2011; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Blood Circulation - drug effects; Cardiac Glycosides - pharmacology; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacology; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Immunology; Internal Medicine; Medical Microbiology; Models, Theoretical; Pharmacology/Toxicology; Review; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Vaccine; blood circulation; Na; steroid-like compound; cardiac glycoside; magnesium lithospermate B; neuroprotection; ginsenoside; traditional Chinese medicine; ATPase inhibitors; K
• ISSN: 1671-4083; 1745-7254
• 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.