ArticleJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism2015
MEK1/2 inhibitor U0126 but not endothelin receptor antagonist clazosentan reduces upregulation of cerebrovascular contractile receptors and delayed cerebral ischemia, and improves outcome after subarachnoid hemorrhage in rats.
Article in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.
- Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental-Clinical Disconnect and the Unmet Need.Neurocritical care · 2020Pooled it
- Clazosentan Affects Temporal Profile of Endothelin-A Expression in Macro- and Microcirculation after Subarachnoid Hemorrhage.Neurologia medico-chirurgica · 2026Article
- Switching Off Vascular MAPK Signaling: A Novel Strategy to Prevent Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage.Translational stroke research · 2025Review
- The MEK Inhibitor Trametinib Improves Outcomes following Subarachnoid Haemorrhage in Female Rats.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Changes in P2YPhysiological reports · 2022Article
- Synergistic effects of a cremophor EL drug delivery system and its U0126 cargo in anDrug delivery · 2019Article
- Article
- A novel multicolor flow-cytometry application for quantitative detection of receptors on vascular smooth muscle cells.PloS one · 2017Article
- Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review.International journal of molecular sciences · 2016Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cerebral vasospasm and late cerebral ischemia (LCI) remain leading causes of mortality in patients experiencing a subarachnoid hemorrhage (SAH). This occurs typically 3 to 4 days after the initial bleeding and peaks at 5 to 7 days. The underlying pathophysiology is still poorly understood. Because SAH is associated with elevated levels of endothelin-1 (ET-1), focus has been on counteracting endothelin receptor activation with receptor antagonists like clazosentan, however, with poor outcome in clinical trials. We hypothesize that inhibition of intracellular transcription signaling will be an effective approach to prevent LCI. Here, we compare the effects of clazosentan versus the MEK1/2 blocker U0126 in a rat model of SAH. Although clazosentan directly inhibits the contractile responses in vivo to ET-1, it did not prevent SAH-induced upregulation of ET receptors in cerebral arteries and did not show a beneficial effect on neurologic outcome. U0126 had no vasomotor effect by itself but counteracts SAH-induced receptor upregulation in cerebral arteries and improved outcome after SAH. We suggest that because SAH induces elevated expression of several contractile receptor subtypes, it is not sufficient to block only one of these (ET receptors) but inhibition of transcriptional MEK1/2-mediated upregulation of several contractile receptors may be a viable way towards alleviating LCI.
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