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RETRACTED ARTICLE: Magnesium lithospermate B alleviates the production of endothelin-1 through an NO-dependent mechanism and reduces experimental vasospasm in rats

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This article was retracted on 17 January 2024

This article has been updated

Abstract

Objective

Magnesium lithospermate B (MLB), a working extract from Salvia miltiorrhiza, was effective against coronary artery disease, ischemic stroke, and chronic renal disease. This study examined the effect of MLB on endothelin-1/endothelial nitric oxide synthase (eNOS) in a subarachnoid hemorrhage (SAH) animal model.

Methods

A rodent double-hemorrhage model was employed. Animals were randomly assigned to five groups (sham, SAH only, vehicle, 10 mg/kg/day MLB treatment, and pretreatment groups). A radiolabeled NOS Assay Kit was used to detect eNOS. Serum and cerebrospinal fluid sampling for ET-1 (ELISA) was measured. The basilar arteries (BAs) were garnered and sliced, and their cross-sectional areas were determined. In addition, NOS inhibitor nitro-arginine methyl ester (L-NAME) was employed in the SAH+ MLB treatment groups.

Results

Significant vasoconstriction was perceived in the SAH group (lumen patency: 44.6%, p < 0.01), but not in the MLB group (lumen patency: 89.3%). The ET-1 level was reduced in the MLP plus SAH group (34%, p < 0.01) when compared with the SAH groups (SAH only and vehicle). MLB dose-dependently increased the level of eNOS when compared with the vehicle plus SAH group. However, the administration of L-NAME reversed the expression of eNOS and vasoconstriction (lumen patency: 56.2%) in the MLB group.

Conclusion

The enhanced expression of eNOS and decreased ET-1 levels in the MLB groups may reflect its anti-spastic effect. In the study of NOS, L-NAME reversed MLB’s anti-vasospastic effect. This finding lends credence to the hypothesis that MLB modulates ET-1 levels through a NOS-dependent mechanism in the pathogenesis of cerebral vasospasm following SAH.

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Change history

Abbreviations

BA:

basilar artery

CSF:

cerebrospinal fluid

DIND:

delayed ischemic neurological deficit

eNOS:

endothelial nitric oxide synthase

IEL:

internal elastic lamina

L-NAME:

nitro-arginine methyl ester

MLB:

magnesium lithospermate B

PDGF:

platelet-derived growth factor

SAH:

subarachnoid hemorrhage

TGF-β1:

transforming growth factor-β1

VEGF:

vascular endothelial growth factor

References

  1. Adams JD, Wang R, Yang J, Lien EJ (2006) Preclinical and clinical examinations of salvia miltiorrhiza and its tanshinones in ischemic conditions. Chin Med 1:3

    Article  PubMed  PubMed Central  Google Scholar 

  2. Arrick DM, Mayhan WG (2010) Inhibition of endothelin-1 receptors improves impaired nitric oxide synthase-dependent dilation of cerebral arterioles in type-1 diabetic rats. Microcirculation 17(6):439–446

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Barone FC, Ohlstein EH, Hunter AJ, Campbell CA, Hadingham SH, Parsons AA, Yang Y, Shohami E (2000) Selective antagonism of endothelin-A-receptors improves outcome in both head trauma and focal stroke in rat. J Cardiovasc Pharmacol 36:S357–S361

    Article  CAS  PubMed  Google Scholar 

  4. Chan K, Chui SH, Wong DY, Ha WY, Chan CL, Wong RN (2004) Protective effects of danshensu from the aqueous extract of salvia miltiorrhiza (danshen) against homocysteine-induced endothelial dysfunction. Life Sci 75:3157–3171

    Article  CAS  PubMed  Google Scholar 

  5. Chang CZ, Wu SC, Kwan AL, Lin CL, Hwang SL (2011) 6-Mercaptopurine reverses experimental vasospasm and alleviates the production of endothelins in NO-independent mechanism-a laboratory study. Acta Neurochir (Wien) 153(4):939–949

    Article  PubMed  Google Scholar 

  6. Chang CZ, Yen CP, Winadi D, Wu SC, Howng SL, Lin TK, Jeng AY, Kassell NF, Kwan AL (2002) Attenuation of hemolysate-induced cerebrovascular endothelial cell injury and of production of endothelin-1 and big endothelin-1 by an endothelin-converting enzyme inhibitor. Surg Neurol 58(3–4):181–188

    Article  PubMed  Google Scholar 

  7. Czóbel M, Kaszaki J, Molnár G, Nagy S, Boros M (2009) Nonspecific inhibition of nitric oxide synthesis evokes endothelin-dependent increases in myocardial contractility. Nitric Oxide 21(3–4):201–209

    Article  PubMed  Google Scholar 

  8. Grasso G (2004) An overview of new pharmacological treatments for cerebrovascular dysfunction after experimental subarachnoid hemorrhage. Brain Res Brain Res Rev 44:49–63

    Article  CAS  PubMed  Google Scholar 

  9. Han JY, Fan JY, Horie Y, Miura S, Cui DH, Ishii H, Hibi T, Tsuneki H, Kimura I (2008) Ameliorating effects of compounds derived from salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacol Ther 117(2):280–295

    Article  CAS  PubMed  Google Scholar 

  10. Hansen-Schwartz J, Vajkoczy P, Macdonald RL, Pluta RM, Zhang JH (2007) Cerebral vasospasm: looking beyond vasoconstriction. Trends Pharmacol Sci 28:252–256

    Article  CAS  PubMed  Google Scholar 

  11. Herrera M, Hong NJ, Ortiz PA, Garvin JL (2009) Endothelin-1 inhibits thick ascending limb transport via Akt-stimulated nitric oxide production. J Biol Chem 284(3):1454–1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hsieh TC, Wu JM (2006) Differential control of growth, cell cycle progression, and gene expression in human estrogen receptor positive mcf-7 breast cancer cells by extracts derived from polysaccharopeptide i'm-yunity and danshen and their combination. Int J Oncol 29:1215–1222

    CAS  PubMed  Google Scholar 

  13. Jeng AY, Mulder P, Kwan AL, Battistini B (2002) Nonpeptidic endothelin-converting enzyme inhibitors and their potential therapeutic applications. Can J Physiol Pharmacol 80(5):440–449

    Article  CAS  PubMed  Google Scholar 

  14. Kang DG, Oh H, Chung HT, Lee HS (2003) Inhibition of angiotensin converting enzyme by lithospermic acid b isolated from radix salviae miltiorrhiza bunge. Phytother Res 17:917–920

    Article  CAS  PubMed  Google Scholar 

  15. Kästner S, Oertel MF, Scharbrodt W, Krause M, Böker DK, Deinsberger W (2005) Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH. Acta Neurochir (Wien) 147(12):1271–1279

    Article  PubMed  Google Scholar 

  16. Kessler IM, Pacheco YG, Lozzi SP, de Araujo AS Jr, Onishi FJ, de Mello PA (2005) Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Surg Neurol 64(Suppl 1:S1):2–5

    Article  Google Scholar 

  17. Keyrouz SG, Diringer MN (2007) Clinical review: prevention and therapy of vasospasm in subarachnoid hemorrhage. Crit Care 11:220

    Article  PubMed  PubMed Central  Google Scholar 

  18. Maier B, Lehnert M, Laurer HL, Marzi I (2007) Biphasic elevation in cerebrospinal fluid and plasma concentrations of endothelin 1 after traumatic brain injury in human patients. Shock 27:610–614

    Article  CAS  PubMed  Google Scholar 

  19. Mitsutomi N, Akashi C, Odagiri J, Matsumura Y (1999) Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. Eur J Pharmacol 364(1):65–73

    Article  CAS  PubMed  Google Scholar 

  20. Mori K, Yamamoto T, Miyazaki M, Hara Y, Aiko Y, Koike N, Sakamoto S, Nakao Y, Esaki T (2010) Optimal cerebrospinal fluid magnesium ion concentration for vasodilatory effect and duration after intracisternal injection of magnesium sulfate solution in a canine subarachnoid hemorrhage model. J Neurosurg 114(4):1–8

    Google Scholar 

  21. Ohkita M, Sugii M, Ka Y, Kitamura A, Mori T, Hayashi T, Takaoka M, Matsumura Y (2006) Differential effects of different statins on endothelin-1 gene expression and endothelial NOS phosphorylation in porcine aortic endothelial cells. Exp Biol Med (Maywood) 231(6):772–776

    CAS  PubMed  Google Scholar 

  22. Ryttlefors M, Enblad P, Ronne-Engström E, Persson L, Ilodigwe D, Macdonald RL (2010) Patient age and vasospasm after subarachnoid hemorrhage. Neurosurgery 67(4):911–917

    Article  PubMed  Google Scholar 

  23. Sercombe R, Dinh YR, Gomis P (2002) Cerebrovascular inflammation following subarachnoid hemorrhage. Jpn J Pharmacol 88:227–249

    Article  CAS  PubMed  Google Scholar 

  24. Turner JD, Mammis A, Prestigiacomo CJ (2010) Erythropoietin for the treatment of subarachnoid hemorrhage: a review. World Neurosurg 73(5):500–507

    Article  PubMed  Google Scholar 

  25. Tzen JT, Jinn TR, Chen YC, Li FY, Cheng FC, Shi LS, She HKh, Chen BC, Hsieh V, Tu ML (2007) Magnesium lithospermate B possesses inhibitory activity on Na+, K+−ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacol Sin 28(5):609–615

    Article  CAS  PubMed  Google Scholar 

  26. Vellimana AK, Milner E, Azad TD, Harries MD, Zhou ML, Gidday JM, Han BH, Zipfel GJ (2011) Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 42(3):776–782

    Article  CAS  PubMed  Google Scholar 

  27. Wang C, Zhao X, Mao S, Wang Y, Cui X, Pu Y (2006) Management of SAH with traditional Chinese medicine in China. Neurol Res 28(4):436–444

    Article  CAS  PubMed  Google Scholar 

  28. Wong GK, Boet R, Poon WS, Chan MT, Gin T, Ng SC, Zee BC (2011) Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage: an updated systemic review and meta-analysis. Crit Care 15(1):R52

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yamamoto T, Esaki T, Nakao Y, Mori K (2010) Efficacy of low-dose tissue-plasminogen activator intracisternal administration for the prevention of cerebral vasospasm after subarachnoid hemorrhage. World Neurosurg 73(6):675–682

    Article  PubMed  Google Scholar 

  30. Yamashiro K, Milsom AB, Duchene J, Panayiotou C, Urabe T, Hattori N, Ahluwalia A (2010) Alterations in nitric oxide and endothelin-1 bioactivity underlie cerebrovascular dysfunction in ApoE-deficient mice. J Cereb Blood Flow Metab 30(8):1494–1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yuen CY, Wong WT, Tian XY, Wong SL, Lau CW, Yu J, Tomlinson B, Yao X, Huang Y (2011) Telmisartan inhibits vasoconstriction via PPAR{gamma}-dependent expression and activation of endothelial nitric oxide synthase. Cardiovasc Res 90(1):122–129

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Y, Clark JF, Pyne-Geithman G, Caruso J (2010) Metallomics study in CSF for putative biomarkers to predict cerebral vasospasm. Metallomics 2(9):628–637

    Article  CAS  PubMed  Google Scholar 

  33. Zhou Z, Wang SQ, Liu Y, Miao AD (2006) Cryptotanshinone inhibits endothelin-1 expression and stimulates nitric oxide production in human vascular endothelial cells. Biochim Biophys Acta 1760:1–9

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

CZC and SCW contributed equally to this work. We thank Ms Shu-Chan Wu of the Neurosurgery Department at Kaohsiung Medical University for her assistance with all of the experiments.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang, Aij-Lie Kwan, Shi-Lin Hwang & Shen-Long Howng

  2. Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang, Shu-Chuan Wu, Aij-Lie Kwan, Shi-Lin Hwang & Shen-Long Howng

  3. Department of Surgery, Kaohsiung Municipal Ta Tung Hospital, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang

Authors
  1. Chih-Zen Chang
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  2. Shu-Chuan Wu
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  3. Aij-Lie Kwan
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  4. Shi-Lin Hwang
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  5. Shen-Long Howng
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Corresponding author

Correspondence to Chih-Zen Chang.

Additional information

Comment

In this study performed by Chang et al., magnesium lithospermate B (MLB), an extract from a traditional Chinese medicine, was evaluated as a drug for reducing experimental vasospasm in rats. Five groups of nine rats were administered the appropriate interventions to determine the efficacy of MLB on vasospasm as shown by histology, the effect of activated eNOS, and then the effect of a selective NOS inhibitor, L-NAME, in relation to MLB. In addition, the effect on CSF endothelin-1 was evaluated.

Dr. Chang's group has shown some promising data on a potential drug for the prevention of experimental vasospasm, as well as elucidated a potential mechanism for its efficacy. This article highlights the importance of NO in vasodilation and thus its importance in vasospasm. Past studies on the effect of eNOS upregulation have been interesting, for example, on the use of simvastatin; however, it is still being evaluated for efficacy. Although it would be helpful to see the effect of MLB in an experimental primate model, or clinical trial, this is an excellent beginning to an interesting venture.

References

1. McGirt MJ et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke, 2002; 332950.

Pulak Ray

Christopher M. Loftus

Philadelphia, PA

This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1007/s00701-024-05906-5"

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Chang, CZ., Wu, SC., Kwan, AL. et al. RETRACTED ARTICLE: Magnesium lithospermate B alleviates the production of endothelin-1 through an NO-dependent mechanism and reduces experimental vasospasm in rats. Acta Neurochir 153, 2211–2217 (2011). https://doi.org/10.1007/s00701-011-1082-6

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  • DOI: https://doi.org/10.1007/s00701-011-1082-6

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