Enhancing the potency of lithospermate B for inhibiting Na + /K + -ATPase activity by forming transition metal ion complexes

Nan Hei Lin, Tse Yu Chung, Feng Yin Li, Hsin An Chen, Jason T C Tzen

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Aim:To determine whether replacing Mg 2+ in magnesium lithospermate B (Mg-LSB) isolated from danshen (Salvia miltiorrhiza) with other metal ions could affect its potency in inhibition of Na + /K + -ATPase activity.Methods:Eight metal ions (Na +, K +, Mg 2+, Cr 3+, Mn 2+, Co 2+, Ni 2+, and Zn 2+) were used to form complexes with LSB. The activity of Na + /K + -ATPase was determined by measuring the amount of inorganic phosphate (Pi) liberated from ATP. Human adrenergic neuroblastoma cell line SH-SY5Y was used to assess the intracellular Ca 2+ level fluctuation and cell viability. The metal binding site on LSB and the binding mode of the metal-LSB complexes were detected by NMR and visible spectroscopy, respectively.Results:The potencies of LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ increased by approximately 5 times compared to the naturally occurring LSB and Mg-LSB. The IC 50 values of Cr-LSB, Mn-LSB, Co-LSB, Ni-LSB, LSB, and Mg-LSB in inhibition of Na + /K + -ATPase activity were 23, 17, 26, 25, 101, and 128 μmol/L, respectively. After treatment of SH-SY5Y cells with the transition metal-LSB complexes (25 μmol/L), the intracellular Ca 2+ level was substantially elevated, and the cells were viable for one day. The transition metals, as exemplified by Co 2+, appeared to be coordinated by two carboxylate groups and one carbonyl group of LSB. Titration of LSB against Co 2+ demonstrated that the Co-LSB complex was formed with a Co 2+:LSB molar ratio of 1:2 or 1:1, when [Co 2+ ] was less than half of the [LSB] or higher than the [LSB], respectively.Conclusion:LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ are stable, non-toxic and more potent in inhibition of Na + /K + -ATPase. The transition metal-LSB complexes have the potential to be superior substitutes for cardiac glycosides in the treatment of congestive heart failure.

Original languageEnglish
Pages (from-to)893-900
Number of pages8
JournalActa Pharmacologica Sinica
Volume34
Issue number7
DOIs
Publication statusPublished - Jul 2013

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Coordination Complexes
Metals
Ions
Salvia miltiorrhiza
Cardiac Glycosides
Neuroblastoma
Adrenergic Agents
Cell Survival
Magnetic Resonance Spectroscopy
Heart Failure
Adenosine Triphosphate
Phosphates
Binding Sites
Cell Line
sodium-translocating ATPase
lithospermate B

Keywords

  • cardiac glycoside
  • congestive heart failure
  • lithospermate B
  • metal complex
  • Na/K-ATPase
  • Salvia miltiorrhiza
  • traditional Chinese medicine
  • transition metal

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Enhancing the potency of lithospermate B for inhibiting Na + /K + -ATPase activity by forming transition metal ion complexes. / Lin, Nan Hei; Chung, Tse Yu; Li, Feng Yin; Chen, Hsin An; Tzen, Jason T C.

In: Acta Pharmacologica Sinica, Vol. 34, No. 7, 07.2013, p. 893-900.

Research output: Contribution to journalArticle

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title = "Enhancing the potency of lithospermate B for inhibiting Na + /K + -ATPase activity by forming transition metal ion complexes",
abstract = "Aim:To determine whether replacing Mg 2+ in magnesium lithospermate B (Mg-LSB) isolated from danshen (Salvia miltiorrhiza) with other metal ions could affect its potency in inhibition of Na + /K + -ATPase activity.Methods:Eight metal ions (Na +, K +, Mg 2+, Cr 3+, Mn 2+, Co 2+, Ni 2+, and Zn 2+) were used to form complexes with LSB. The activity of Na + /K + -ATPase was determined by measuring the amount of inorganic phosphate (Pi) liberated from ATP. Human adrenergic neuroblastoma cell line SH-SY5Y was used to assess the intracellular Ca 2+ level fluctuation and cell viability. The metal binding site on LSB and the binding mode of the metal-LSB complexes were detected by NMR and visible spectroscopy, respectively.Results:The potencies of LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ increased by approximately 5 times compared to the naturally occurring LSB and Mg-LSB. The IC 50 values of Cr-LSB, Mn-LSB, Co-LSB, Ni-LSB, LSB, and Mg-LSB in inhibition of Na + /K + -ATPase activity were 23, 17, 26, 25, 101, and 128 μmol/L, respectively. After treatment of SH-SY5Y cells with the transition metal-LSB complexes (25 μmol/L), the intracellular Ca 2+ level was substantially elevated, and the cells were viable for one day. The transition metals, as exemplified by Co 2+, appeared to be coordinated by two carboxylate groups and one carbonyl group of LSB. Titration of LSB against Co 2+ demonstrated that the Co-LSB complex was formed with a Co 2+:LSB molar ratio of 1:2 or 1:1, when [Co 2+ ] was less than half of the [LSB] or higher than the [LSB], respectively.Conclusion:LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ are stable, non-toxic and more potent in inhibition of Na + /K + -ATPase. The transition metal-LSB complexes have the potential to be superior substitutes for cardiac glycosides in the treatment of congestive heart failure.",
keywords = "cardiac glycoside, congestive heart failure, lithospermate B, metal complex, Na/K-ATPase, Salvia miltiorrhiza, traditional Chinese medicine, transition metal",
author = "Lin, {Nan Hei} and Chung, {Tse Yu} and Li, {Feng Yin} and Chen, {Hsin An} and Tzen, {Jason T C}",
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T1 - Enhancing the potency of lithospermate B for inhibiting Na + /K + -ATPase activity by forming transition metal ion complexes

AU - Lin, Nan Hei

AU - Chung, Tse Yu

AU - Li, Feng Yin

AU - Chen, Hsin An

AU - Tzen, Jason T C

PY - 2013/7

Y1 - 2013/7

N2 - Aim:To determine whether replacing Mg 2+ in magnesium lithospermate B (Mg-LSB) isolated from danshen (Salvia miltiorrhiza) with other metal ions could affect its potency in inhibition of Na + /K + -ATPase activity.Methods:Eight metal ions (Na +, K +, Mg 2+, Cr 3+, Mn 2+, Co 2+, Ni 2+, and Zn 2+) were used to form complexes with LSB. The activity of Na + /K + -ATPase was determined by measuring the amount of inorganic phosphate (Pi) liberated from ATP. Human adrenergic neuroblastoma cell line SH-SY5Y was used to assess the intracellular Ca 2+ level fluctuation and cell viability. The metal binding site on LSB and the binding mode of the metal-LSB complexes were detected by NMR and visible spectroscopy, respectively.Results:The potencies of LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ increased by approximately 5 times compared to the naturally occurring LSB and Mg-LSB. The IC 50 values of Cr-LSB, Mn-LSB, Co-LSB, Ni-LSB, LSB, and Mg-LSB in inhibition of Na + /K + -ATPase activity were 23, 17, 26, 25, 101, and 128 μmol/L, respectively. After treatment of SH-SY5Y cells with the transition metal-LSB complexes (25 μmol/L), the intracellular Ca 2+ level was substantially elevated, and the cells were viable for one day. The transition metals, as exemplified by Co 2+, appeared to be coordinated by two carboxylate groups and one carbonyl group of LSB. Titration of LSB against Co 2+ demonstrated that the Co-LSB complex was formed with a Co 2+:LSB molar ratio of 1:2 or 1:1, when [Co 2+ ] was less than half of the [LSB] or higher than the [LSB], respectively.Conclusion:LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ are stable, non-toxic and more potent in inhibition of Na + /K + -ATPase. The transition metal-LSB complexes have the potential to be superior substitutes for cardiac glycosides in the treatment of congestive heart failure.

AB - Aim:To determine whether replacing Mg 2+ in magnesium lithospermate B (Mg-LSB) isolated from danshen (Salvia miltiorrhiza) with other metal ions could affect its potency in inhibition of Na + /K + -ATPase activity.Methods:Eight metal ions (Na +, K +, Mg 2+, Cr 3+, Mn 2+, Co 2+, Ni 2+, and Zn 2+) were used to form complexes with LSB. The activity of Na + /K + -ATPase was determined by measuring the amount of inorganic phosphate (Pi) liberated from ATP. Human adrenergic neuroblastoma cell line SH-SY5Y was used to assess the intracellular Ca 2+ level fluctuation and cell viability. The metal binding site on LSB and the binding mode of the metal-LSB complexes were detected by NMR and visible spectroscopy, respectively.Results:The potencies of LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ increased by approximately 5 times compared to the naturally occurring LSB and Mg-LSB. The IC 50 values of Cr-LSB, Mn-LSB, Co-LSB, Ni-LSB, LSB, and Mg-LSB in inhibition of Na + /K + -ATPase activity were 23, 17, 26, 25, 101, and 128 μmol/L, respectively. After treatment of SH-SY5Y cells with the transition metal-LSB complexes (25 μmol/L), the intracellular Ca 2+ level was substantially elevated, and the cells were viable for one day. The transition metals, as exemplified by Co 2+, appeared to be coordinated by two carboxylate groups and one carbonyl group of LSB. Titration of LSB against Co 2+ demonstrated that the Co-LSB complex was formed with a Co 2+:LSB molar ratio of 1:2 or 1:1, when [Co 2+ ] was less than half of the [LSB] or higher than the [LSB], respectively.Conclusion:LSB complexed with Cr 3+, Mn 2+, Co 2+, or Ni 2+ are stable, non-toxic and more potent in inhibition of Na + /K + -ATPase. The transition metal-LSB complexes have the potential to be superior substitutes for cardiac glycosides in the treatment of congestive heart failure.

KW - cardiac glycoside

KW - congestive heart failure

KW - lithospermate B

KW - metal complex

KW - Na/K-ATPase

KW - Salvia miltiorrhiza

KW - traditional Chinese medicine

KW - transition metal

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U2 - 10.1038/aps.2013.32

DO - 10.1038/aps.2013.32

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EP - 900

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