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Blockade of K ATP Channels Reduces Endothelial Hyperpolarization and Leukocyte Recruitment upon Reperfusion After Hypoxia
Author(s) -
Figura M.,
Chilton L.,
Liacini A.,
Viskovic M. Maric,
Phan V.,
Knight D.,
Millar T. M.,
Patel K.,
Kubes P.,
Giles W. R.,
Tibbles L. A.
Publication year - 2009
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2009.02553.x
Subject(s) - medicine , reperfusion injury , glibenclamide , ischemia , hypoxia (environmental) , transplantation , hyperpolarization (physics) , pharmacology , inflammation , intravital microscopy , microcirculation , anesthesia , endocrinology , physics , nuclear magnetic resonance , chemistry , organic chemistry , oxygen , nuclear magnetic resonance spectroscopy , diabetes mellitus
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.