Blockade of KATP Channels Reduces Endothelial Hyperpolarization and Leukocyte Recruitment upon Reperfusion After Hypoxia

American Journal of Transplantation - Tập 9 - Trang 687 - 2009
W.R. Giles1, K. Patel2, V. Phan2, L.A. Tibbles2,3, M. Figura2, P. Kubes2, T.M. Millar4, D. Knight2, L. Chilton1, M. Maric Viskovic2, A. Liacini2
1Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada
2Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
3Department of Medicine, Division of Nephrology, Calgary Health Region, Calgary, Alberta, Canada
4University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK

Tóm tắt

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 KATP antagonist glibenclamide (Glyburide™). Further, we show that glibenclamide can reduce leukocyte recruitment in vitro under physiologic flow conditions. ATP-regulated potassium channels (KATP) 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.

Từ khóa

#Endothelial cell hyperpolarization #ischemia/reperfusion injury #KATP channels #neutrophil recruitment

Tài liệu tham khảo

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