CoChat
Sign Up
Cited by 20Nitric Oxide and Endothelin EffectsIntracranial Aneurysms: Treatment and ComplicationsTakotsubo Cardiomyopathy and Associated Phenomena

In vitro and in vivo effects of probucol on hydrolysis of asymmetric dimethyl L-arginine and vasospasm in primates

Pluta, Ryszard M., Jung, Carla S., Harvey-White, Judith, Whitehead, Anne, Shilad, Sabrina, Espey, Michael G., Oldfield, Edward H.·2005·Journal of neurosurgery
DOI 10.3171/jns.2005.103.4.0731
Open this paper in CoChat — free account

Abstract

OBJECT: Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl L-arginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), are associated with delayed vasospasm after subarachnoid hemorrhage (SAH); however, the source, cellular mechanisms, and pharmacological inhibition of ADMA production following SAH are unknown. METHODS: In an in vitro experiment involving human umbilical vein endothelial cells (HUVECs), the authors examined mechanisms potentially responsible for increased ADMA levels during vasospasm and investigated whether this increase can be inhibited pharmacologically. In a second study, an in vivo experiment, the authors used probucol, which effectively inhibited ADMA increase in HUVEC cultures in vitro, in a randomized double-blind placebo-controlled experiment in a primate model of delayed cerebral vasospasm after SAH. Oxidized low-density lipids (OxLDLs; positive control; p < 0.02) and bilirubin oxidation products (BOXes; p < 0.01), but not oxyhemoglobin (p = 0.74), increased ADMA levels in HUVECs. Probucol inhibited changes in ADMA levels evoked by either OxLDLs (p < 0.001) or BOXes (p < 0.01). Comparable changes were observed in cell lysates. In vivo probucol (100 mg/kg by mouth daily) did not alter serum ADMA levels on Days 7, 14, and 21 after SAH compared with levels before SAH, and these levels were not different from those observed in the placebo group (p = 0.3). Despite achieving therapeutic levels in plasma and measurable levels in CSF, probucol neither prevented increased CSF ADMA levels nor the development of vasospasm after SAH. Increased CSF ADMA and decreased nitrite levels in both groups were strongly associated with the degree of delayed vasospasm after SAH (correlation coefficient [CC] 0.5, 95% confidence interval [CI] 0.19-0.72, p < 0.002 and CC -0.43, 95% CI -0.7 to -0.05, p < 0.03, respectively). CONCLUSIONS: Bilirubin oxidation products, but not oxyhemoglobin, increased ADMA levels in the HUVEC. Despite its in vitro ability to lower ADMA levels, probucol failed to inhibit increased CSF ADMA and decreased nitrite levels, and it did not prevent delayed vasospasm in a primate SAH model.

Integrity signals

Registry

Crossref · 10.3171/jns.2005.103.4.0731

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Pluta, R. M., Jung, C. S., Harvey-White, J., Whitehead, A., Shilad, S., Espey, M. G., & Oldfield, E. H.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Journal of neurosurgery
Publisher
Journal of Neurosurgery Publishing Group (JNSPG)
Published
2005-10
Volume
103
Issue
4
Pages
731-738
ISSN
0022-3085 (ISSN-L)
DOI
10.3171/jns.2005.103.4.0731
OpenAlex
W2006211189
Cited by
20
References
73
Citations by year
2023: 1 · 2021: 1 · 2015: 1 · 2013: 2
FWCI
1.60
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of neurosurgery (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Neurology › Intracranial Aneurysms: Treatment and Complications
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Takotsubo Cardiomyopathy and Associated Phenomena
Keywords
probucol, delayed cerebral vasospasm, subarachnoid hemorrhage, endothelial nitric oxide synthase, oxidized LDL, oxyhemoglobin, nitrite, human umbilical vein endothelial cells, nonhuman primate model
MeSH terms
Animals, Antioxidants, Arginine, Bilirubin, Double-Blind Method, Enzyme Inhibitors, Hydrolysis, Macaca fascicularis, Oxidation-Reduction, Placebos, Probucol, Random Allocation, Subarachnoid Hemorrhage, Time Factors, Umbilical Veins, Lipid Peroxidation, Cell Culture Techniques, Nitric Oxide Synthase, Vasospasm, Intracranial, Endothelial Cells, Nitric Oxide Synthase Type III

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review