title: Active ingredients in Chinese medicines promoting blood circulation as Na+/K+ -ATPase inhibitors.
abstract: 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.
authors.affiliation: Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, China.
authors.forename: Ronald J Y
authors.initials: RJ
authors.lastname: Chen
authors.forename: Tzyy-rong
authors.initials: TR
authors.lastname: Jinn
authors.forename: Yi-ching
authors.initials: YC
authors.lastname: Chen
authors.forename: Tse-yu
authors.initials: TY
authors.lastname: Chung
authors.forename: Wei-hung
authors.initials: WH
authors.lastname: Yang
authors.forename: Jason T C
authors.initials: JT
authors.lastname: Tzen
mesh_terms: D000818:Animals; D001775:Blood Circulation / Q000187:drug effects*; D002301:Cardiac Glycosides / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008962:Models, Theoretical; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
chemical_list: D002301:Cardiac Glycosides; D004365:Drugs, Chinese Herbal; D000254:Sodium-Potassium-Exchanging ATPase