Full Text:   <3433>

CLC number: R96

On-line Access: 2011-10-08

Received: 2011-03-04

Revision Accepted: 2011-05-19

Crosschecked: 2011-09-14

Cited: 8

Clicked: 6993

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2011 Vol.12 No.10 P.835-845


Iptakalim, an ATP-sensitive potassium channel opener, confers neuroprotection against cerebral ischemia/reperfusion injury in rats by protecting neurovascular unit cells

Author(s):  Yu-hua Ran, Hai Wang

Affiliation(s):  Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, China, Thadweik Academy of Medicine, Beijing 100039, China

Corresponding email(s):   wh9558@yahoo.cn

Key Words:  Neurovascular unit, Cerebral ischemia/reperfusion (I/R) injury, ATP-sensitive potassium channel opener, Neuroprotection, Apoptosis

Yu-hua Ran, Hai Wang. Iptakalim, an ATP-sensitive potassium channel opener, confers neuroprotection against cerebral ischemia/reperfusion injury in rats by protecting neurovascular unit cells[J]. Journal of Zhejiang University Science B, 2011, 12(10): 835-845.

@article{title="Iptakalim, an ATP-sensitive potassium channel opener, confers neuroprotection against cerebral ischemia/reperfusion injury in rats by protecting neurovascular unit cells",
author="Yu-hua Ran, Hai Wang",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Iptakalim, an ATP-sensitive potassium channel opener, confers neuroprotection against cerebral ischemia/reperfusion injury in rats by protecting neurovascular unit cells
%A Yu-hua Ran
%A Hai Wang
%J Journal of Zhejiang University SCIENCE B
%V 12
%N 10
%P 835-845
%@ 1673-1581
%D 2011
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1100067

T1 - Iptakalim, an ATP-sensitive potassium channel opener, confers neuroprotection against cerebral ischemia/reperfusion injury in rats by protecting neurovascular unit cells
A1 - Yu-hua Ran
A1 - Hai Wang
J0 - Journal of Zhejiang University Science B
VL - 12
IS - 10
SP - 835
EP - 845
%@ 1673-1581
Y1 - 2011
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1100067

Objective: To investigate the role of iptakalim, an ATP-sensitive potassium channel opener, in transient cerebral ischemia/reperfusion (I/R) injury and its involved mechanisms. Methods: Intraluminal occlusion of middle cerebral artery (MCAO) in a rat model was used to investigate the effect of iptakalim at different time points. Infarct volume was measured by staining with 2,3,5-triphenyltetrazolium chloride, and immunohistochemistry was used to evaluate the expressions of Bcl-2 and Bax. In vitro, neurovascular unit (NVU) cells, including rat primary cortical neurons, astrocytes, and cerebral microvascular endothelial cells, were cultured and underwent oxygen-glucose deprivation (OGD). The protective effect of iptakalim on NVU cells was investigated by cell viability and injury assessments, which were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and release of lactate dehydrogenase. Caspase-3, Bcl-2 and Bax mRNA expressions were evaluated by real-time polymerase chain reaction (PCR). Results: Administration of iptakalim 0 or 1 h after reperfusion significantly reduced infarct volumes, improved neurological scores, and attenuated brain edema after cerebral I/R injury. Iptakalim treatment (0 h after reperfusion) also reduced caspase-3 expression and increased the ratio of Bcl-2 to Bax by immunohistochemistry. Iptakalim inhibited OGD-induced cell death in cultured neurons and astrocytes, and lactate dehydrogenase release from cerebral microvascular endothelial cells. Iptakalim reduced mRNA expression of caspase-3 and increased the ratio of Bcl-2 to Bax in NVU cells. Conclusions: Iptakalim confers neuroprotection against cerebral I/R injury by protecting NVU cells via inhibiting of apoptosis.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Abdel-Hamid, K.M., Baimbridge, K.G., 1997. The effects of artificial calcium buffers on calcium responses and glutamate-mediated excitotoxicity in cultured hippocampal neurons. Neuroscience, 81(3):673-687.

[2]Chan, P.H., 1996. Role of oxidants in ischemic brain damage. Stroke, 27(6):1124-1129.

[3]Chen, Y.P., Qiu, C.R., Wang, H., 2004. Cardiovascular pharmacological characterization of novel 2,3-dimethyl-2-butylamine derivatives in rats. Life Sci., 75(17):2131-2142.

[4]Chen, Y.P., Cui, W.Y., Wang, H., 2006. Selective actions of iptakalim on the subtypes of KATP channels. Chin. Pharmacol. Bull, 22(3):278-284.

[5]Diarra, A., Sheldon, C., Brett, C.L., Baimbridge, K.G., Church, J., 1999. Anoxia-evoked intracellular pH and Ca2+ concentration changes in cultured postnatal rat hippocampal neurons. Neuroscience, 93(3):1003-1016.

[6]Domoki, F., Kis, B., Nagy, K., Farkas, E., Busija, D.W., Bari, F., 2005. Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets. Am. J. Physiol., 289(1):H368-H373.

[7]Dunn-Meynell, A.A., Rawson, N.E., Levin, B.E., 1998. Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain. Brain Res., 814(1-2):41-54.

[8]Girn, H.R., Ahilathirunayagam, S., Mavor, A.I., Homer-Vanniasinkam, S., 2007. Reperfusion syndrome: cellular mechanisms of microvascular dysfunction and potential therapeutic strategies. Vasc. Endovascular Surg., 41(4):277-293.

[9]Graham, S.H., Chen, J., 2001. Programmed cell death in cerebral ischemia. J. Cereb. Blood Flow Metab., 21(2):99-109.

[10]Green, D.R., Reed, J.C., 1998. Mitochondria and apoptosis. Science, 281(5381):1309-1312.

[11]Hamprecht, B., Löffler, F., 1985. Primary glial cultures as a model for studying hormone action. Methods Enzymol., 109:341-345.

[12]Hu, X.L., Olsson, T., Johansson, I.M., Brannstrom, T., Wester, P., 2004. Dynamic changes of the anti- and pro-apoptotic proteins Bcl-w, Bcl-2, and Bax with Smac/Diablo mitochondrial release after photothrombotic ring stroke in rats. Eur. J. Neurosci., 20(5):1177-1188.

[13]Janigro, D., West, G.A., Gordon, E.L., Winn, H.R., 1993. ATP-sensitive K+ channels in rat aorta and brain microvascular endothelial cells. Am. J. Physiol., 265(3 Pt 1):C812-C821.

[14]Kis, B., Kaiya, H., Nishi, R., Deli, M.A., Abraham, C.S., Yanagita, T., Isse, T., Gotoh, S., Kobayashi, H., Wada, A., et al., 2002. Cerebral endothelial cells are a major source of adrenomedullin. J. Neuroendocrinol., 14(4):283-293.

[15]Kis, B., Snipes, J.A., Simandle, S.A., Busija, D.W., 2005. Acetaminophen-sensitive prostaglandin production in rat cerebral endothelial cells. Am. J. Physiol., 288(4):R897-R902.

[16]Kowaltowski, A.J., Castilho, R.F., Vercesi, A.E., 2001. Mitochondrial permeability transition and oxidative stress. FEBS Lett., 495(1-2):12-15.

[17]Kroemer, G., 2003. Mitochondrial control of apoptosis: an introduction. Biochem. Biophys. Res. Commun., 304(3):433-435.

[18]Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S., Wang, X., 1997. Cytochrome C and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 91(4):479-489.

[19]Li, Y., Chopp, M., Jiang, N., Yao, F., Zaloga, C., 1995. Temporal profile of in situ DNA fragmentation after transient middle cerebral artery occlusion in the rat. J. Cereb. Blood Flow Metab., 15(3):389-397.

[20]Linnik, M.D., Zobrist, R.H., Hatfield, M.D., 1993. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke, 24(12):2002-2008; discussion 2008-2009.

[21]Liss, B., Bruns, R., Roeper, J., 1999. Alternative sulfonylurea receptor expression defines metabolic sensitivity of KATP channels in dopaminergic midbrain neurons. EMBO J., 18(4):833-846.

[22]Lo, E.H., Rosenberg, G.A., 2009. The neurovascular unit in health and disease: introduction. Stroke, 40(3):S2-S3.

[23]Makins, R., Ballinger, A., 2003. Gastrointestinal side effects of drugs. Expert Opin. Drug Saf., 2(4):421-429.

[24]Mattson, M.P., Duan, W., Pedersen, W.A., Culmsee, C., 2001. Neurodegenerative disorders and ischemic brain diseases. Apoptosis, 6(1-2):69-81.

[25]Mederos y Schnitzler, M., Derst, C., Daut, J., Preisig-Müller, R., 2000. ATP-sensitive potassium channels in capillaries isolated from guinea-pig heart. J. Physiol., 525(2):307-317.

[26]Roof, R.L., Schielke, G.P., Ren, X., Hall, E.D., 2001. A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke, 32(11):2648-2657.

[27]Sato, T., Sasaki, N., O′Rourke, B., Marban, E., 2000. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels. J. Am. Coll. Cardiol., 35(2):514-518.

[28]Seino, S., Miki, T., 2004. Gene targeting approach to clarification of ion channel function: studies of Kir6.x null mice. J. Physiol., 554(2):295-300.

[29]Shimizu, K., Lacza, Z., Rajapakse, N., Horiguchi, T., Snipes, J., Busija, D.W., 2002. MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat. Am. J. Physiol., 283(3):H1005-H1011.

[30]Simard, J.M., Chen, M., 2004. Regulation by sulfanylurea receptor type 1 of a non-selective cation channel involved in cytotoxic edema of reactive astrocytes. J. Neurosurg. Anesthesiol., 16(1):98-99.

[31]Swanson, R.A., Sharp, F.R., 1994. Infarct measurement methodology. J. Cereb. Blood Flow Metab., 14(4):697-698.

[32]Tsuchiya, D., Hong, S., Matsumori, Y., Shiina, H., Kayama, T., Swanson, R.A., Dillman, W.H., Liu, J., Panter, S.S., Weinstein, P.R., 2003. Overexpression of rat heat shock protein 70 is associated with reduction of early mitochondrial cytochrome C release and subsequent DNA fragmentation after permanent focal ischemia. J. Cereb. Blood Flow Metab., 23(6):718-727.

[33]Wang, H., Zhang, Y.L., Tang, X.C., Feng, H.S., Hu, G., 2004. Targeting ischemic stroke with a novel opener of ATP-sensitive potassium channels in the brain. Mol. Pharmacol., 66(5):1160-1168.

[34]Wang, H., Tang, Y., Wang, L., Long, C.L., Zhang, Y.L., 2007. ATP-sensitive potassium channel openers and 2,3-dimethyl-2-butylamine derivatives. Curr. Med. Chem., 14(2):133-155.

[35]Yamada, K., Ji, J.J., Yuan, H., Miki, T., Sato, S., Horimoto, N., Shimizu, T., Seino, S., Inagaki, N., 2001. Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science, 292(5521):1543-1546.

[36]Yanamoto, H., Nagata, I., Hashimoto, N., Kikuchi, H., 1998. Three-vessel occlusion using a micro-clip for the proximal left middle cerebral artery produces a reliable neocortical infarct in rats. Brain Res. Brain Res. Protoc., 3(2):209-220.

[37]Yang, G.Y., Betz, A.L., 1994. Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats. Stroke, 25(8):1658-1664; discussion 1664-1655.

[38]Yoshida, H., Feig, J.E., Morrissey, A., Ghiu, I.A., Artman, M., Coetzee, W.A., 2004. KATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits. J. Mol. Cell. Cardiol., 37(4):857-869.

[39]Zhang, S., Zhou, F., Ding, J.H., Zhou, X.Q., Sun, X.L., Hu, G., 2007. ATP-sensitive potassium channel opener iptakalim protects against MPP-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. J. Neurochem., 103(2):569-579.

[40]Zhu, H.L., Luo, W.Q., Wang, H., 2008. Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels. Neuroscience, 157(4):884-894.

Open peer comments: Debate/Discuss/Question/Opinion


Cuiping Liu@nanfang hosptial<bullebell@163.com>

2011-10-11 10:16:19

this is a very interesting paperm and I want to read the fulltext

Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE