title: Cardioprotective effects of irbesartan in polymicrobial sepsis : The role of the p38MAPK/NF-κB signaling pathway.
abstract: BACKGROUND
  Sepsis is a systemic inflammatory response usually correlated with multi-organ failure. Myocardial dysfunction is one of the adverse outcomes in septic patients and results in high mortality rates. The aim of this study was to investigate the impact of irbesartan in attenuation of cardiac depression during polymicrobial sepsis via decreased activation of the phospho-p38MAPK/nuclear factor (NF)-κB signaling pathway.
  
  
  METHODS
  A model of polymicrobial sepsis induced via cecal ligation and puncture (CLP) with 8- to 12-week-old albino mice was used. Mice were treated with i.p. irbesartan (3 mg/kg) 1 h before CLP. Using a micro-tipped transducer catheter, the following hemodynamic parameters were evaluated after CLP: heart rate, ejection fraction, left ventricular (LV) end-diastolic pressure, LV systolic pressure, and cardiac output. Plasma levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), and cardiac troponin I (cTn-I), were measured via ELISA analysis. The degree of p38MAPK and NF-κB phosphorylation was assessed via Western blotting.
  
  
  RESULTS
  Mice treated with irbesartan displayed improvement in LV function (ejection fraction: 42.4 ± 1.1% vs. 27.8 ± 3% in CLP mice). The attenuation of cardiac depression in irbesartan-treated mice was associated with lower levels of MCP-1 in plasma and a reduction in the levels of TNF-alpha, IL-1beta, and IL-6. Furthermore, irbesartan-treated mice displayed lower expression levels of p38-MAPK and NF-κB phosphorylation.
  
  
  CONCLUSIONS
  Irbesartan can attenuate cardiac dysfunction during polymicrobial sepsis possibly via a reduction of proinflammatory cytokines through decreased activation of the p38MAPK/NF-κB pathways.
authors.affiliation: Department of Medicine, Muthanna Medical College, Samawah, Iraq. yousif_ghaly@yahoo.com.|Anschutz | Medical School, University of Colorado, Denver, USA. yousif_ghaly@yahoo.com.
authors.forename: N G
authors.initials: NG
authors.lastname: Yousif
authors.affiliation: Department of Pharmacology and Therapeutics, Kufa Medical College, University Kufa, Kufa, Iraq.
authors.forename: N R
authors.initials: NR
authors.lastname: Hadi
authors.affiliation: Department of Thoracic Surgery, Kufa Medical College, University Kufa, Kufa, Iraq.
authors.forename: F
authors.initials: F
authors.lastname: Al-Amran
authors.affiliation: Department of Pharmacology and Therapeutics, Kufa Medical College, University Kufa, Kufa, Iraq.
authors.forename: Q A
authors.initials: QA
authors.lastname: Zigam
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D060085:Coinfection / Q000097:blood / Q000188:drug therapy*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007274:Injections, Intraperitoneal; D000077405:Irbesartan / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011292:Premedication; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002316:Cardiotonic Agents; D016207:Cytokines; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; D000077405:Irbesartan
keywords: Acute-phase reaction; Anti-hypertensive agents; Cytokines; Hemodynamics; Septicemia