title: Hepatic cytoprotection by nitric oxide and the cGMP pathway after ischaemia-reperfusion in the rat.
abstract: Many studies in diverse models suggest that nitric oxide (NO) may be protective against liver injury due to ischaemia-reperfusion (IR). We evaluated, in an experimental in vivo model of rat liver partial ischaemia, the effects of pretreatment by an NO donor (spermineNONOate, 5mg/kg), and exogenous cGMP (8Br-cGMP, 16 mg/kg) or an endogenous cGMP producer (ANP, 10 microg/kg), to assess their beneficial effects. After 6h of reperfusion, 8Br-cGMP completely prevented the adverse effect of Nomega-nitro-L-arginine (10mg/kg) and 8Br-cGMP alone showed a protective action on both hepatocytes (AST, -25%, LDH, -55%) and endothelial cells (plasma hyaluronic acid (HA), -30%). ANP caused a marked decrease in AST and LDH activities only after 1h of reperfusion (AST, -30%, LDH, -40%). Pretreatment with spermineNONOate prevented hepatocyte injury after 1 and 6h of reperfusion (AST, -22%, LDH, -27%). However, neither spermineNONOate nor ANP had any protective effect on endothelial cell damage. These results confirm the beneficial effect of an NO donor and strongly suggest the implication of a cGMP pathway that does not involve a blockade of inflammatory cytokines production (IL-6 generation was unaffected by 8Br-cGMP pre-treatment). In our model, 8Br-cGMP showed a greater protective effect than ANP or spermineNONOate and so might be used to prevent hepatic injury after IR. Finally, we propose a schematic representation of the different routes for the actions of NO in protecting the liver against IR damage.
authors: Laboratoire d'Endocrinologie, Faculté des Sciences Pharmaceutiques et Biologiques, and INSERM UMR S 530, UFR Biomédicale, Université René Descartes, Paris, France.
authors: Charles Henry
authors: CH
authors: Cottart
authors: Valérie
authors: V
authors: Nivet-Antoine
authors: Louis
authors: L
authors: Do
authors: Ghassan
authors: G
authors: Al-Massarani
authors: Geneviéve
authors: G
authors: Descamps
authors: François
authors: F
authors: Xavier-Galen
authors: Jean-Pierre
authors: JP
authors: Clot
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006820:Hyaluronic Acid / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009589:Nitrogen Oxides; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; C091861:spermine nitric oxide complex; D013096:Spermine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D006820:Hyaluronic Acid; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester