title: Comparative effects of recombinant human activated protein C and dexamethasone in experimental septic shock.
abstract: OBJECTIVE
  To compare the effects of recombinant human activated protein C (APC) and glucocorticoids alone and in combination in non-anesthetized resuscitated septic shock induced by cecal ligation and puncture (CLP) on (a) survival, (b) hemodynamics, and (c) vascular reactivity. The effects of treatments on major cellular pathways likely implicated were also studied.
  
  
  METHODS
  Four hours after CLP, rats were continuously infused with either saline (10 ml/kg/h), saline + APC, saline + dexamethasone (Dexa), or saline + APC + Dexa. Eighteen hours after CLP, arterial pressure, cardiac output, nitrite/nitrate ratio, and lactate concentrations were measured. Aortic rings and mesenteric arteries were isolated and mounted in a myograph, after which arterial contractility and endothelium-dependent relaxation were measured in the presence or absence of nitric oxide synthase (NOS) or cyclooxygenase (COX) inhibitors. Protein expression was assessed by Western blotting. Aorta NO and superoxide anion content were measured by electron paramagnetic resonance.
  
  
  RESULTS
  All treatments improved hemodynamic parameters and vascular reactivity and decreased lactate and nitrite/nitrate levels. In treated aorta and mesenteric arteries, contractility and endothelial dysfunction were improved. This effect was associated with an increase in the phosphorylated form of protein kinase B as well as an increase in COX vasodilatory pathways and a decrease in iNOS expression suggesting that these pathways are implicated in the vascular effect of the treatments. CLP was associated with a marked increase in aortic NO and superoxide anion content (p < 0.05), which were decreased by APC and Dexa and totally abolished by APC + Dexa (p < 0.01). Survival length was significantly increased by the APC-Dexa combination.
  
  
  CONCLUSIONS
  Both APC and Dexa improve arterial contractility and endothelial dysfunction resulting from septic shock in rats. Moreover, their combination increased the length of survival. These findings provide important insights into the mechanisms underlying APC- and/or Dexa-induced improvements of arterial dysfunction during septic shock.
authors.affiliation: Groupe Choc, Contrat Avenir INSERM, Faculté de Médecine, Nancy-Université, Nancy, France.
authors.forename: Youcef
authors.initials: Y
authors.lastname: Bouazza
authors.forename: Nacira
authors.initials: N
authors.lastname: Sennoun
authors.forename: Charlène
authors.initials: C
authors.lastname: Strub
authors.forename: Véronique
authors.initials: V
authors.lastname: Regnault
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gibot
authors.forename: Ferhat
authors.initials: F
authors.lastname: Meziani
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.forename: Bruno
authors.initials: B
authors.lastname: Levy
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000925:Anticoagulants; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D005938:Glucocorticoids; D011486:Protein C; D011994:Recombinant Proteins; D009569:Nitric Oxide; D003907:Dexamethasone