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Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia

Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia
Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia
Ischemia/reperfusion injury in renal transplantation leads to slow or initial nonfunction, and predisposes to acute and chronic rejection. In fact, severe ischemia reperfusion injury can significantly reduce graft survival, even with modern immunosuppressive agents. One of the mechanisms by which ischemia/reperfusion causes injury is activation of endothelial cells resulting in inflammation. Although several therapies can be used to prevent leukocyte recruitment to ischemic vessels (e.g. antiadhesion molecule antibodies), there have been no clinical treatments reported that can prevent initial immediate neutrophil recruitment upon reperfusion. Using intravital microscopy, we describe abrogation of immediate neutrophil recruitment to ischemic microvessels by the K(ATP) antagonist glibenclamide (Glyburide). Further, we show that glibenclamide can reduce leukocyte recruitment in vitro under physiologic flow conditions. ATP-regulated potassium channels (K(ATP)) are important in the control of cell membrane polarization. Here we describe profound hyperpolarization of endothelial cells during hypoxia, and the reduction of this hyperpolarization using glibenclamide. These findings suggest that control of endothelial membrane potential during ischemia may be an important therapeutic tool in avoiding ischemia/reperfusion injury, and therefore, enhancing transplant long-term function.
1600-6135
687-696
Figura, M.
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Chilton, L.
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Liacini, A.
da22d086-34ee-47a3-ad18-8f1268730335
Viskovic, M.M.
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Phan, V.
eaf533de-8806-47f0-81b5-7f1ad8652118
Knight, D.
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Millar, T.M.
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Patel, K.
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Kubes, P.
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Giles, W.R.
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Tibbles, L.A.
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Maric, M.
1901bda6-04d2-4a9c-923e-6bf578a780f2
Figura, M.
c3fcd119-39cc-4a0a-95fd-cb23e2b0d751
Chilton, L.
6a0b87b5-6349-47ea-97ec-faae24ff06a5
Liacini, A.
da22d086-34ee-47a3-ad18-8f1268730335
Viskovic, M.M.
b7402b9a-024b-4c47-969c-c3824e752ee2
Phan, V.
eaf533de-8806-47f0-81b5-7f1ad8652118
Knight, D.
b86f5d4f-7344-4da9-b020-313f6d467acf
Millar, T.M.
ec88510c-ad88-49f6-8b2d-4277c84c1958
Patel, K.
4abba9fd-ff3d-42f1-a4fe-c43e0f22367f
Kubes, P.
304928cc-902a-40db-bc68-d86a1a8c938f
Giles, W.R.
d4b0fae4-0abf-4870-8487-f440e9e00dee
Tibbles, L.A.
f4161f4a-0e60-4c03-a334-099dcf87535c
Maric, M.
1901bda6-04d2-4a9c-923e-6bf578a780f2

Figura, M., Chilton, L., Liacini, A., Viskovic, M.M., Phan, V., Knight, D., Millar, T.M., Patel, K., Kubes, P., Giles, W.R., Tibbles, L.A. and Maric, M. (2009) Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia. American Journal of Transplantation, 9 (4), 687-696. (doi:10.1111/j.1600-6143.2009.02553.x).

Record type: Article

Abstract

Ischemia/reperfusion injury in renal transplantation leads to slow or initial nonfunction, and predisposes to acute and chronic rejection. In fact, severe ischemia reperfusion injury can significantly reduce graft survival, even with modern immunosuppressive agents. One of the mechanisms by which ischemia/reperfusion causes injury is activation of endothelial cells resulting in inflammation. Although several therapies can be used to prevent leukocyte recruitment to ischemic vessels (e.g. antiadhesion molecule antibodies), there have been no clinical treatments reported that can prevent initial immediate neutrophil recruitment upon reperfusion. Using intravital microscopy, we describe abrogation of immediate neutrophil recruitment to ischemic microvessels by the K(ATP) antagonist glibenclamide (Glyburide). Further, we show that glibenclamide can reduce leukocyte recruitment in vitro under physiologic flow conditions. ATP-regulated potassium channels (K(ATP)) are important in the control of cell membrane polarization. Here we describe profound hyperpolarization of endothelial cells during hypoxia, and the reduction of this hyperpolarization using glibenclamide. These findings suggest that control of endothelial membrane potential during ischemia may be an important therapeutic tool in avoiding ischemia/reperfusion injury, and therefore, enhancing transplant long-term function.

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Published date: 2009
Organisations: Infection Inflammation & Immunity

Identifiers

Local EPrints ID: 73122
URI: http://eprints.soton.ac.uk/id/eprint/73122
ISSN: 1600-6135
PURE UUID: d35620d0-df21-48ba-8101-2882a790ee03
ORCID for T.M. Millar: ORCID iD orcid.org/0000-0002-4539-2445

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Date deposited: 02 Mar 2010
Last modified: 13 Mar 2024 21:54

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Contributors

Author: M. Figura
Author: L. Chilton
Author: A. Liacini
Author: M.M. Viskovic
Author: V. Phan
Author: D. Knight
Author: T.M. Millar ORCID iD
Author: K. Patel
Author: P. Kubes
Author: W.R. Giles
Author: L.A. Tibbles
Author: M. Maric

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