Steroid-like compounds in Chinese medicines promote blood circulation via inhibition of Na+/K+ -ATPase.
OBJECTIVE
To examine if steroid-like compounds found in many Chinese medicinal products conventionally used for the promotion of blood circulation may act as active components via the same molecular mechanism triggered by cardiac glycosides, such as ouabain.


METHODS
The inhibitory potency of ouabain and the identified steroid-like compounds on Na(+)/K(+)-ATPase activity was examined and compared. Molecular modeling was exhibited for the docking of these compounds to Na(+)/K(+)-ATPase.


RESULTS
All the examined steroid-like compounds displayed more or less inhibition on Na(+)/K(+)-ATPase, with bufalin (structurally almost equivalent to ouabain) exhibiting significantly higher inhibitory potency than the others. In the pentacyclic triterpenoids examined, ursolic acid and oleanolic acid were moderate inhibitors of Na(+)/K(+)-ATPase, and their inhibitory potency was comparable to that of ginsenoside Rh2. The relatively high inhibitory potency of ursolic acid or oleanolic acid was due to the formation of a hydrogen bond between its carboxyl group and the Ile322 residue in the deep cavity close to two K(+) binding sites of Na(+)/K(+)-ATPase. Moreover, the drastic difference observed in the inhibitory potency of ouabain, bufalin, ginsenoside Rh2, and pentacyclic triterpenoids is ascribed mainly to the number of hydrogen bonds and partially to the strength of hydrophobic interaction between the compounds and residues around the deep cavity of Na(+)/K(+)-ATPase.


CONCLUSIONS
Steroid-like compounds seem to contribute to therapeutic effects of many cardioactive Chinese medicinal products. Chinese herbs, such as Prunella vulgaris L, rich in ursolic acid, oleanolic acid and their glycoside derivatives may be adequate sources for cardiac therapy via effective inhibition on Na(+)/K(+)-ATPase.
Chen
Ronald J Y
RJ
Graduate Institute of Biotechnology National Chung Hsing University, Taichung, Taiwan, China.
Chung
Tse-yu
TY
Li
Feng-yin
FY
Yang
Wei-hung
WH
Jinn
Tzyy-rong
TR
Tzen
Jason T C
JT
D000818:Animals; D001775:Blood Circulation / Q000187:drug effects*; D002301:Cardiac Glycosides / Q000737:chemistry / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010042:Ouabain / Q000737:chemistry / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002301:Cardiac Glycosides; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D013256:Steroids; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase