Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 32, Issue 6, Pages 1035-1045Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2012.14
Keywords
circulating factors; hyperglycemic stroke; middle cerebral artery; peroxynitrite; rats; vascular tone
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Funding
- NIH, NINDS [RO1 NS043316, RO1 NS045940]
- NHLBI [PO1 HL095488]
- Totman Medical Research Trust
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We investigated mechanisms by which circulating factors during hyperglycemic (HG) stroke affect cerebrovascular function and the role of peroxynitrite in stroke outcome. Middle cerebral arteries (MCAs) were isolated from male Wistar rats and perfused with plasma from rats that were hyperglycemic for 5 to 6 days by streptozotocin and underwent either MCA occlusion (HG MCAO) or Sham surgery (HG Sham) compared with MCA perfused with physiologic saline (No plasma). Myogenic responses and endothelial function were compared in untreated MCA (n=8/group) or with inhibitors of NADPH oxidase (apocynin; n=8), peroxynitrite (FeTMPyP; n=8) or endothelin-1 (ET-1)(A) (60-123; n=8). Finally, animals were treated in vivo before reperfusion after mild (<68% cerebral blood flow (CBF) decrease) or severe (>68% CBF decrease) MCAO with FeTMPyP (n=12) or vehicle (n=12) and CBF and infarction measured. The HG MCAO plasma increased tone in MCA versus No plasma (P<0.05) that was reversed by FeTMPyP, but not by apocynin or 60-123. The HG Sham plasma also increased tone in MCA (P<0.05) that was reversed by BQ-123 only. In vivo, FeTMPyP was neuroprotective during mild, but not severe ischemia. These results show that circulating factors in plasma can affect cerebrovascular function through peroxynitrite generation and ET-1. In addition, peroxynitrite decomposition improves stroke outcome acutely during mild, but not severe HG ischemia. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 1035-1045; doi:10.1038/jcbfm.2012.14; published online 29 February 2012
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