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Evidence for blood‐brain barrier Na‐K‐Cl cotransport, Na/H exchange and Na‐HCO 3 cotransport involvement in hyperglycemia exacerbation of cerebral edema formation in ischemic stroke (685.3)
Author(s) -
Chechneva Olga,
Yuen Natalie,
Tsai YiChen,
Chen YiJe,
Anderson Steven,
O'Donnell Martha
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.685.3
Subject(s) - cotransporter , bumetanide , cerebral edema , chemistry , endocrinology , medicine , ischemia , mannitol , sodium , biochemistry , organic chemistry
Hyperglycemia (HG) exacerbates cerebral edema formation in ischemic stroke and worsens clinical outcome through poorly understood mechanisms. Our previous studies provided evidence that the blood‐brain barrier (BBB) Na transporters Na‐K‐Cl cotransport (NKCC), Na/H exchange (NHE) and Na‐HCO3 cotransport (NBC) are stimulated by ischemic factors, causing increased secretion of Na and water into the brain and consequent cerebral edema formation. In the present study we examined the effects of HG on cerebral microvascular endothelial cell (CMEC) NKCC, NHE and NBC expression and activity, as well the effects of ischemic factors on the Na transporter activities following HG exposures using methods that included Western blot, qRT‐PCR, radioisotopic flux assays and microspectrofluorometry. We found that HG (30 vs 5 mM glucose; 6, 24, 48 hr and 7 d) increased abundance of bovine and human CMEC NKCC1, NHE1 and NBCn1. These exposures to HG also significantly increased CMEC NKCC, NHE and NBC activities. mRNA levels of NHE1 but not NKCC1 or NBCn1 were significantly increased by 6 and 24 hr of HG. Osmotic controls (with mannitol or NaCl) had no effect on abundance, activity or mRNA levels. HG also caused a greater increase in ischemic factor stimulation of these Na transporter activities. Finally, MRI studies showed that bumetanide and HOE‐642 inhibition of NKCC and NHE reduced HG‐worsened edema in rats with cerebral ischemia. Grant Funding Source : Supported by NIH and ADA