Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke


Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NCCa-ATP channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NCCa-ATP but not KATP channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NCCa-ATP channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: SUR1 is upregulated in MCA stroke model.
Figure 2: SUR1 but not Kir6.1 or Kir6.2 is transcriptionally upregulated in MCA stroke model.
Figure 3: Association of Sp1 and SUR1 promoter region in cerebral ischemia.
Figure 4: Expression of functional NCCa-ATP channels in cerebral ischemia.
Figure 5: Glibenclamide reduces mortality, edema and infarct volume, and improves cerebral blood flow in MCA stroke models.
Figure 6: Tissue distribution of BODIPY-glibenclamide in MCA stroke model.

Accession codes




  1. Ayata, C. & Ropper, A.H. Ischaemic brain oedema. J. Clin. Neurosci. 9, 113–124 (2002).

    Article  Google Scholar 

  2. Seino, S. ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu. Rev. Physiol. 61, 337–362 (1999).

    Article  CAS  Google Scholar 

  3. Chen, M., Dong, Y. & Simard, J.M. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J. Neurosci. 23, 8568–8577 (2003).

    Article  CAS  Google Scholar 

  4. Chen, M. & Simard, J.M. Cell swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J. Neurosci. 21, 6512–6521 (2001).

    Article  CAS  Google Scholar 

  5. Mathews, K.S. et al. Rapid quantification of ischaemic injury and cerebroprotection in brain slices using densitometric assessment of 2,3,5-triphenyltetrazolium chloride staining. J. Neurosci. Methods 102, 43–51 (2000).

    Article  CAS  Google Scholar 

  6. Chen, H., Chopp, M., Schultz, L., Bodzin, G. & Garcia, J.H. Sequential neuronal and astrocytic changes after transient middle cerebral artery occlusion in the rat. J. Neurol. Sci. 118, 109–116 (1993).

    Article  CAS  Google Scholar 

  7. Treherne, J.M. & Ashford, M.L. The regional distribution of sulphonylurea binding sites in rat brain. Neuroscience 40, 523–531 (1991).

    Article  CAS  Google Scholar 

  8. Karschin, C., Ecke, C., Ashcroft, F.M. & Karschin, A. Overlapping distribution of K(ATP) channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain. FEBS Lett. 401, 59–64 (1997).

    Article  CAS  Google Scholar 

  9. Ashfield, R. & Ashcroft, S.J. Cloning of the promoters for the beta-cell ATP-sensitive K-channel subunits Kir6.2 and SUR1. Diabetes 47, 1274–1280 (1998).

    CAS  PubMed  Google Scholar 

  10. Hernandez-Sanchez, C., Ito, Y., Ferrer, J., Reitman, M. & LeRoith, D. Characterization of the mouse sulfonylurea receptor 1 promoter and its regulation. J. Biol. Chem. 274, 18261–18270 (1999).

    Article  CAS  Google Scholar 

  11. Findlay, I. Effects of pH upon the inhibition by sulphonylurea drugs of ATP-sensitive K+ channels in cardiac muscle. J. Pharmacol. Exp. Ther. 262, 71–79 (1992).

    CAS  PubMed  Google Scholar 

  12. Zunkler, B.J., Trube, G. & Panten, U. How do sulfonylureas approach their receptor in the B-cell plasma membrane? Naunyn Schmiedebergs Arch. Pharmacol. 340, 328–332 (1989).

    Article  CAS  Google Scholar 

  13. Nedergaard, M., Kraig, R.P., Tanabe, J. & Pulsinelli, W.A. Dynamics of interstitial and intracellular pH in evolving brain infarct. Am. J. Physiol. 260, R581–R588 (1991).

    Article  CAS  Google Scholar 

  14. Fujita, A. & Kurachi, Y. Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers. Pharmacol. Ther. 85, 39–53 (2000).

    Article  CAS  Google Scholar 

  15. Gribble, F.M. & Reimann, F. Sulphonylurea action revisited: the post-cloning era. Diabetologia 46, 875–891 (2003).

    Article  CAS  Google Scholar 

  16. Proks, P., Reimann, F., Green, N., Gribble, F. & Ashcroft, F. Sulfonylurea stimulation of insulin secretion. Diabetes 51 Suppl 3, S368–S376 (2002).

    Article  CAS  Google Scholar 

  17. Li, P.A., Shamloo, M., Smith, M.L., Katsura, K. & Siesjo, B.K. The influence of plasma glucose concentrations on ischemic brain damage is a threshold function. Neurosci. Lett. 177, 63–65 (1994).

    Article  CAS  Google Scholar 

  18. Wass, C.T. & Lanier, W.L. Glucose modulation of ischemic brain injury: review and clinical recommendations. Mayo Clin. Proc. 71, 801–812 (1996).

    Article  CAS  Google Scholar 

  19. Doerfler, A., Schwab, S., Hoffmann, T.T., Engelhorn, T. & Forsting, M. Combination of decompressive craniectomy and mild hypothermia ameliorates infarction volume after permanent focal ischemia in rats. Stroke 32, 2675–2681 (2001).

    Article  CAS  Google Scholar 

  20. Lindauer, U., Vogt, J., Schuh-Hofer, S., Dreier, J.P. & Dirnagl, U. Cerebrovascular vasodilation to extraluminal acidosis occurs via combined activation of ATP-sensitive and Ca2+-activated potassium channels. J. Cereb. Blood Flow Metab. 23, 1227–1238 (2003).

    Article  CAS  Google Scholar 

  21. Tomiyama, Y., Brian, J.E., Jr. & Todd, M.M. Cerebral blood flow during hemodilution and hypoxia in rats: role of ATP-sensitive potassium channels. Stroke 30, 1942–1947 (1999).

    Article  CAS  Google Scholar 

  22. Schwanstecher, M., Loser, S., Chudziak, F., Bachmann, C. & Panten, U. Photoaffinity labeling of the cerebral sulfonylurea receptor using a novel radioiodinated azidoglibenclamide analogue. J. Neurochem. 63, 698–708 (1994).

    Article  CAS  Google Scholar 

  23. Dorschner, H., Brekardin, E., Uhde, I., Schwanstecher, C. & Schwanstecher, M. Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure. Mol. Pharmacol. 55, 1060–1066 (1999).

    Article  CAS  Google Scholar 

  24. Xu, Q., Ji, Y.S. & Schmedtje, J.F., Jr. Sp1 increases expression of cyclooxygenase-2 in hypoxic vascular endothelium. Implications for the mechanisms of aortic aneurysm and heart failure. J. Biol. Chem. 275, 24583–24589 (2000).

    Article  CAS  Google Scholar 

  25. Kaluz, S., Kaluzova, M. & Stanbridge, E.J. Expression of the hypoxia marker carbonic anhydrase IX is critically dependent on SP1 activity. Identification of a novel type of hypoxia-responsive enhancer. Cancer Res. 63, 917–922 (2003).

    CAS  PubMed  Google Scholar 

  26. Young, W. & Constantini, S. The Neurobiology of Central Nervous System Trauma (eds. Salzman, S.K. & Faden, A.I.) (Oxford University Press, New York, 1994).

    Google Scholar 

  27. Wang, Y. et al. Brain tissue sodium is a ticking clock telling time after arterial occlusion in rat focal cerebral ischemia. Stroke 31, 1386–1391 (2000).

    Article  CAS  Google Scholar 

  28. Toomey, J.R. et al. Inhibition of factor IX(a) is protective in a rat model of thromboembolic stroke. Stroke 33, 578–585 (2002).

    Article  CAS  Google Scholar 

  29. Nakabayashi, K. et al. Evaluation of particulate embolic materials with MR imaging, scanning electron microscopy, and phase-contrast microscopy. AJNR Am. J. Neuroradiol. 18, 485–491 (1997).

    CAS  PubMed  Google Scholar 

  30. Kawamura, S., Yasui, N., Shirasawa, M. & Fukasawa, H. Rat middle cerebral artery occlusion using an intraluminal thread technique. Acta Neurochir. (Wien) 109, 126–132 (1991).

    Article  CAS  Google Scholar 

  31. Hua, Y., Keep, R.F., Hoff, J.T. & Xi, G. Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron. J. Cereb. Blood Flow Metab. 23, 1448–1454 (2003).

    Article  CAS  Google Scholar 

  32. Gerzanich, V. et al. Alternative splicing of cGMP-dependent protein kinase I in angiotensin-hypertension: novel mechanism for nitrate tolerance in vascular smooth muscle. Circ. Res. 93, 805–812 (2003).

    Article  CAS  Google Scholar 

  33. Perillan, P.R., Chen, M., Potts, E.A. & Simard, J.M. Transforming growth factor-beta 1 regulates Kir2.3 inward rectifier K+ channels via phospholipase C and protein kinase C-delta in reactive astrocytes from adult rat brain. J. Biol. Chem. 277, 1974–1980 (2002).

    Article  CAS  Google Scholar 

  34. Anisimov, S.V., Tarasov, K.V., Riordon, D., Wobus, A.M. & Boheler, K.R. SAGE identification of differentiation responsive genes in P19 embryonic cells induced to form cardiomyocytes in vitro. Mech. Dev. 117, 25–74 (2002).

    Article  CAS  Google Scholar 

  35. Tsankova, N.M., Kumar, A. & Nestler, E.J. Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J. Neurosci. 24, 5603–5610 (2004).

    Article  CAS  Google Scholar 

  36. Hainsworth, A.H., Spadoni, F., Lavaroni, F., Bernardi, G. & Stefani, A. Effects of extracellular pH on the interaction of sipatrigine and lamotrigine with high-voltage-activated (HVA) calcium channels in dissociated neurones of rat cortex. Neuropharmacology 40, 784–791 (2001).

    Article  CAS  Google Scholar 

Download references


This work was supported by grants (to J.M.S.) from the National Institute of Neurological Disorders and Stroke (NS048260), National Heart, Lung, and Blood Institute (HL082517) and by a Merit Review Grant from the Veterans Affairs (Baltimore Veterans Affairs, Baltimore, Maryland, USA).

Author information

Authors and Affiliations


Corresponding author

Correspondence to J Marc Simard.

Ethics declarations

Competing interests

The authors have applied for a US patent, “A novel non-selective cation channel in neural cells and methods for treating brain swelling” (application number 10/391,561).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Simard, J., Chen, M., Tarasov, K. et al. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nat Med 12, 433–440 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing