title: Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia.
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.
authors.affiliation: Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Figura
authors.forename: L
authors.initials: L
authors.lastname: Chilton
authors.forename: A
authors.initials: A
authors.lastname: Liacini
authors.forename: M Maric
authors.initials: MM
authors.lastname: Viskovic
authors.forename: V
authors.initials: V
authors.lastname: Phan
authors.forename: D
authors.initials: D
authors.lastname: Knight
authors.forename: T M
authors.initials: TM
authors.lastname: Millar
authors.forename: K
authors.initials: K
authors.lastname: Patel
authors.forename: P
authors.initials: P
authors.lastname: Kubes
authors.forename: W R
authors.initials: WR
authors.lastname: Giles
authors.forename: L A
authors.initials: LA
authors.lastname: Tibbles
mesh_terms: D000818:Animals; D002415:Cats; D002462:Cell Membrane / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005780:Gelatin / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced / Q000503:physiopathology*; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D007962:Leukocytes / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D020110:Pinacidil / Q000494:pharmacology; D015427:Reperfusion Injury / Q000517:prevention & control*; D014471:Umbilical Veins / Q000187:drug effects / Q000502:physiology
chemical_list: D054086:KATP Channels; D020110:Pinacidil; D005780:Gelatin; D005905:Glyburide