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  Propentdyopents as heme degradation intermediates constrict mouse cerebral arterioles and are present in the cerebrospinal fluid of patients with subarachnoid hemorrhage

Joerk, A., Ritter, M., Langguth, N., Seidel, R. A., Freitag, D., Herrmann, K.-H., et al. (2019). Propentdyopents as heme degradation intermediates constrict mouse cerebral arterioles and are present in the cerebrospinal fluid of patients with subarachnoid hemorrhage. Circulation Research, 124(12), e101-e114. doi:10.1161/CIRCRESAHA.118.314160.

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 Creators:
Joerk, Alexander, Author
Ritter, Marcel, Author
Langguth, Niklas, Author
Seidel, Raphael Andreas, Author
Freitag, Diana, Author
Herrmann, Karl-Heinz, Author
Schaefgen, Anna, Author
Ritter, Marvin, Author
Günther, Milena, Author
Sommer, Charline, Author
Braemer, Dirk, Author
Walter, Jan, Author
Ewald, Christian, Author
Kalff, Rolf, Author
Reichenbach, Jürgen Rainer, Author
Westerhausen, Matthias, Author
Pohnert, Georg1, Author           
Witte, Otto Wilhelm, Author
Holthoff, Knut, Author
Affiliations:
1External Organizations, ou_persistent22              

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 Abstract: Rationale: Delayed ischemic neurological deficit is the most common cause of neurological impairment and
unfavorable prognosis in patients with subarachnoid hemorrhage (SAH). Despite the existence of neuroimaging
modalities that depict the onset of the accompanying cerebral vasospasm, preventive and therapeutic options
are limited and fail to improve outcome owing to an insufficient pathomechanistic understanding of the delayed
perfusion deficit. Previous studies have suggested that BOXes (bilirubin oxidation end products), originating from
released heme surrounding ruptured blood vessels, are involved in arterial vasoconstriction. Recently, isolated
intermediates of oxidative bilirubin degradation, known as PDPs (propentdyopents), have been considered as
potential additional effectors in the development of arterial vasoconstriction.
Objective: To investigate whether PDPs and BOXes are present in hemorrhagic cerebrospinal fluid and involved in
the vasoconstriction of cerebral arterioles.
Methods and Results: Via liquid chromatography/mass spectrometry, we measured increased PDP and BOX
concentrations in cerebrospinal fluid of SAH patients compared with control subjects. Using differential interference
contrast microscopy, we analyzed the vasoactivity of PDP isomers in vitro by monitoring the arteriolar diameter
in mouse acute brain slices. We found an arteriolar constriction on application of PDPs in the concentration
range that occurs in the cerebrospinal fluid of patients with SAH. By imaging arteriolar diameter changes using
2-photon microscopy in vivo, we demonstrated a short-onset vasoconstriction after intrathecal injection of either
PDPs or BOXes. Using magnetic resonance imaging, we observed a long-term PDP-induced delay in cerebral
perfusion. For all conditions, the arteriolar narrowing was dependent on functional big conductance potassium
channels and was absent in big conductance potassium channels knockout mice.
Conclusions: For the first time, we have quantified significantly higher concentrations of PDP and BOX isomers in
the cerebrospinal fluid of patients with SAH compared to controls. The vasoconstrictive effect caused by PDPs in
vitro and in vivo suggests a hitherto unrecognized pathway contributing to the pathogenesis of delayed ischemic
deficit in patients with SAH.

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 Dates: 2019-04-032019-06-072019
 Publication Status: Issued
 Pages: -
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 Rev. Type: -
 Identifiers: Other: EXT660
DOI: 10.1161/CIRCRESAHA.118.314160
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Title: Circulation Research
  Other : Circ. Res.
Source Genre: Journal
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Publ. Info: Baltimore, Md. : Lippincott Williams & Wilkins
Pages: - Volume / Issue: 124 (12) Sequence Number: - Start / End Page: e101 - e114 Identifier: ISSN: 0009-7330
CoNE: https://pure.mpg.de/cone/journals/resource/954925390276