title: Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury.
abstract: NO (nitric oxide) may protect the liver from IR (ischaemia/reperfusion) injury. RIPC (remote ischaemic preconditioning) also protects against liver IR injury; however, the molecular mediator(s) of RIPC are currently unknown. The aim of the present study was to assess the role of NO in hindlimb RIPC-induced protection against liver IR injury. Mice were allocated to the following groups: sham group; RIPC group (six cycles of 4×4 min IR of hindlimb); IR group [40 min lobar (70%) hepatic ischaemia and 2-h reperfusion]; RIPC+IR group (RIPC followed by IR group procedures); and C-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt]+RIPC+IR group [C-PTIO (a direct NO scavenger) was administered, followed by the RIPC+IR group procedure]. Hepatic MBF (microcirculatory blood flow) was measured throughout the experiment. Circulating NOx (nitrite and nitrate) levels, plasma liver transaminases, hepatic histopathological and TEM (transmission electron microscopy) studies were performed at the end of the experiment. NOx concentrations were significantly elevated (P<0.05) in the RIPC and RIPC+IR groups. Compared with liver IR alone, RIPC+IR preserved hepatic MBF during liver reperfusion (P<0.05). In contrast, C-PTIO+RIPC+IR reduced MBF compared with RIPC+IR (P<0.05). RIPC+IR reduced plasma transaminases (P<0.05), and histopathological and ultrastructural features of injury compared with IR alone. The protective effects of RIPC+IR in reducing liver IR injury were abrogated in the group that received antecedent C-PTIO (C-PTIO+RIPC+IR). In conclusion, NO is an essential mediator of the protection afforded by hindlimb RIPC against liver IR injury. The mechanisms underlying this protection involve preservation of the sinusoidal structure and maintenance of blood flow through the hepatic microcirculation.
authors.affiliation: Liver Transplantation and Hepatobiliary Unit, Department of Electron Microscopy, Royal Free Hospital, and Academic Department of Surgery, University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abu-Amara
authors.forename: Shi Yu
authors.initials: SY
authors.lastname: Yang
authors.forename: Alberto
authors.initials: A
authors.lastname: Quaglia
authors.forename: Peter
authors.initials: P
authors.lastname: Rowley
authors.forename: Achala
authors.initials: A
authors.lastname: de Mel
authors.forename: Niteen
authors.initials: N
authors.lastname: Tapuria
authors.forename: Alexander
authors.initials: A
authors.lastname: Seifalian
authors.forename: Brian
authors.initials: B
authors.lastname: Davidson
authors.forename: Barry
authors.initials: B
authors.lastname: Fuller
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D007093:Imidazoles / Q000494:pharmacology; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply* / Q000648:ultrastructure; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D008854:Microscopy, Electron; D009569:Nitric Oxide / Q000097:blood / Q000502:physiology*; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000637:Transaminases / Q000097:blood
chemical_list: D001565:Benzoates; D007093:Imidazoles; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D000637:Transaminases