title: Postconditioning protects against human endothelial ischaemia-reperfusion injury via subtype-specific KATP channel activation and is mimicked by inhibition of the mitochondrial permeability transition pore.
abstract: OBJECTIVE
  Intermittent early reperfusion (ischaemic postconditioning; PostC) reduces ischaemia-reperfusion (IR) injury. Using an in vivo model of endothelial IR injury in humans, we sought to determine the role of K(ATP) channels in PostC and whether inhibition of the mitochondrial permeability transition pore (mPTP) at the onset of reperfusion protected against endothelial IR injury.
  
  
  RESULTS
  Endothelial function (EF) in healthy volunteers was assessed using vascular ultrasound to measure the percentage increase in the diameter of the brachial artery in response to reactive hyperaemia [flow-mediated dilatation (FMD)]. In resistance vessels, venous occlusion plethysmography was used to measure the dilator response to acetylcholine (ACh) [area under ACh dose-response curve (ACh AUC)]. Measurements were made before and after IR injury. Ischaemic postconditioning consisted of three 10 s cycles of alternating ischaemia and reperfusion in the first minute of reperfusion. Oral glibenclamide and glimepiride were used to determine the role of K(ATP) channel subtypes in PostC. Intra-arterial cyclosporine was used to determine the role of mPTP in endothelial IR injury. Ischaemia-reperfusion reduced EF in the brachial artery (FMD 7.1 ± 0.9% pre-IR, 2.8 ± 0.4% post-IR; P < 0.001) and resistance vessels [ACh AUC (×10(4)) 2.1 ± 0.4 pre-IR, 1.5 ± 0.2 post-IR; P < 0.05]. Ischaemic postconditioning preserved EF in the brachial artery [FMD 6.8 ± 0.9% (P < 0.001 vs. post-IR)] and resistance vessels [ACh AUC (×10(4)) 1.9 ± 0.2 (P < 0.001 vs. post-IR)]. Protection by PostC was abolished by glibenclamide in the brachial artery [FMD 3.3 ± 0.2% (P < 0.001 vs. post-IR + PostC)] and in resistance vessels [ACh AUC (×10(4)) 1.1 ± 0.2 (P < 0.001 vs. post-IR + PostC)], whereas glimepiride had no effect. Cyclosporine preserved EF after IR injury in the resistance vessels [ACh AUC (×10(4)) 1.4 ± 0.2 post-IR vs. 2.2 ± 0.3 post-IR + cyclosporine; P < 0.05].
  
  
  CONCLUSIONS
  Protection by PostC against endothelial IR injury in humans depends on K(ATP) channel activation and is mimicked by inhibition of the mPTP at reperfusion.
authors.affiliation: Centre for Clinical Pharmacology, University College London, The Rayne Institute, 5 University Street, London, UK. m.okorie@ucl.ac.uk
authors.forename: Michael I
authors.initials: MI
authors.lastname: Okorie
authors.forename: Deepash D
authors.initials: DD
authors.lastname: Bhavsar
authors.forename: Deborah
authors.initials: D
authors.lastname: Ridout
authors.forename: Marietta
authors.initials: M
authors.lastname: Charakida
authors.forename: John E
authors.initials: JE
authors.lastname: Deanfield
authors.forename: Stavros P
authors.initials: SP
authors.lastname: Loukogeorgakis
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: MacAllister
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D001916:Brachial Artery / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D057775:Ischemic Postconditioning; D054086:KATP Channels / Q000378:metabolism*; D008026:Ligation; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D015427:Reperfusion Injury / Q000517:prevention & control*; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D054086:KATP Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013453:Sulfonylurea Compounds; D014665:Vasodilator Agents; C057619:glimepiride; D016572:Cyclosporine; D000109:Acetylcholine; D005905:Glyburide