title: Cirrhosis is associated with development of tolerance to cardiac chronotropic effect of endotoxin in rats.
abstract: OBJECTIVE
  Sepsis is a common complication of cirrhosis with a high mortality. Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction, which is known as cirrhotic cardiomyopathy and might be linked to endotoxaemia. This study was aimed to explore the hypothesis that the inflammatory response induced by administration of low dose of lipopolysaccharide (LPS) exacerbates cardiac chronotropic dysfunction in cirrhotic rats; and if so, whether this is associated with altered cardiac toll-like receptor expression.
  
  
  METHODS
  Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. Four weeks after bile duct ligation or sham surgery, the subjects were given intraperitoneal injection of either saline or LPS (0.1 mg/kg). Five hours after LPS injection, the atria were isolated and spontaneously beating rate and chronotropic responsiveness to β-adrenergic stimulation was assessed using standard organ bath. The expression of toll-like receptor 4 (TLR4) was assessed the atria using immunohistochemistry as well as quantitative RT-PCR.
  
  
  RESULTS
  LPS injection could induce a significant hypo-responsiveness to adrenergic stimulation in sham-operated rats. However, in cirrhotic rats, the chronotropic responses did not change after acute injection of LPS. Immunohistochemical study showed that TLR4 is mainly expressed in the myocardium in control atria and its expression is markedly decreased in myocardial layer following chronic bile duct ligation.
  
  
  CONCLUSIONS
  Our data showed that cirrhosis is associated with development of tolerance to cardiac chronotropic effect of LPS in rats and this might be caused by altered localization of TLR4 in myocardium.
authors: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Farahnaz
authors: F
authors: Jazaeri
authors: Seyed M
authors: SM
authors: Tavangar
authors: Mahmoud
authors: M
authors: Ghazi-Khansari
authors: Mohammad R
authors: MR
authors: Khorramizadeh
authors: Ali R
authors: AR
authors: Mani
authors: Ahmad R
authors: AR
authors: Dehpour
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology*; D017931:DNA Primers / Q000235:genetics; D004361:Drug Tolerance / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity*; D008103:Liver Cirrhosis / Q000150:complications* / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D017931:DNA Primers; D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4