title: Compared effects of inhibition and exogenous administration of hydrogen sulphide in ischaemia-reperfusion injury.
abstract: BACKGROUND
  Haemorrhagic shock is associated with an inflammatory response consecutive to ischaemia-reperfusion (I/R) that leads to cardiovascular failure and organ injury. The role of and the timing of administration of hydrogen sulphide (H2S) remain uncertain. Vascular effects of H2S are mainly mediated through K+ATP-channel activation. Herein, we compared the effects of D,L-propargylglycine (PAG), an inhibitor of H2S production, as well as sodium hydrosulphide (NaHS), an H2S donor, on haemodynamics, vascular reactivity and cellular pathways in a rat model of I/R. We also compared the haemodynamic effects of NaHS administered before and 10 minutes after reperfusion.
  
  
  METHODS
  Mechanically ventilated and instrumented rats were bled during 60 minutes in order to maintain mean arterial pressure at 40 ± 2 mmHg. Ten minutes prior to retransfusion, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl) or PAG (50 mg/kg). PNU, a pore-forming receptor inhibitor of K+ATP channels, was used to assess the role of K+ATP channels.
  
  
  RESULTS
  Shock and I/R induced a decrease in mean arterial pressure, lactic acidosis and ex vivo vascular hyporeactivity, which were attenuated by NaHS administered before reperfusion and PNU but not by PAG and NaHS administered 10 minutes after reperfusion. NaHS also prevented aortic inducible nitric oxide synthase expression and nitric oxide production while increasing Akt and endothelial nitric oxide synthase phosphorylation. NaHS reduced JNK activity and p-P38/P38 activation, suggesting a decrease in endothelial cell activation without variation in ERK phosphorylation. PNU + NaHS increased mean arterial pressure when compared with NaHS or PNU alone, suggesting a dual effect of NaHS on vascular reactivity.
  
  
  CONCLUSIONS
  NaHS when given before reperfusion protects against the effects of haemorrhage-induced I/R by acting primarily through a decrease in both proinflammatory cytokines and inducible nitric oxide synthase expression and an upregulation of the Akt/endothelial nitric oxide synthase pathway.
authors.forename: Khodor
authors.initials: K
authors.lastname: Issa
authors.forename: Antoine
authors.initials: A
authors.lastname: Kimmoun
authors.forename: Solène
authors.initials: S
authors.lastname: Collin
authors.forename: Frederique
authors.initials: F
authors.lastname: Ganster
authors.forename: Sophie
authors.initials: S
authors.lastname: Fremont-Orlowski
authors.forename: Pierre
authors.initials: P
authors.lastname: Asfar
authors.forename: Paul-Michel
authors.initials: PM
authors.lastname: Mertes
authors.forename: Bruno
authors.initials: B
authors.lastname: Levy
mesh_terms: D000140:Acidosis, Lactic / Q000503:physiopathology; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D064426:Gasotransmitters / Q000494:pharmacology / Q000627:therapeutic use*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010766:Phosphorylation; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D012771:Shock, Hemorrhagic / Q000503:physiopathology; D013440:Sulfides / Q000494:pharmacology; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000480:Alkynes; D016207:Cytokines; D064426:Gasotransmitters; D054086:KATP Channels; D009025:Morpholines; D013440:Sulfides; D014662:Vasoconstrictor Agents; C082658:U 37883A; C009055:propargylglycine; D000255:Adenosine Triphosphate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; C025451:sodium bisulfide; D000218:Adamantane; D005998:Glycine; D009638:Norepinephrine; D006862:Hydrogen Sulfide