title: Experimental examination of anti-inflammatory effects of a 5-HT3 receptor antagonist, tropisetron, and concomitant effects on autonomic nervous function in a rat sepsis model.
abstract: BACKGROUND
  A 5-HT(3) receptor antagonist, tropisetron, has been reported to exhibit an anti-inflammatory effect in chronic inflammatory diseases by antagonizing a particular subtype of serotonin receptors. We investigated whether overproduction of cytokines could be controlled by intervention with tropisetron in an animal model of sepsis and also examined the effects of tropisetron on autonomic nervous activity.
  
  
  METHODS
  Sixty-eight adult male Sprague-Dawley rats were used (28 for examination of cytokine production and autonomic nervous activity; 40 for survival analysis). Each part of the study involved 4 animal groups, including two control groups without drug administration. Sepsis was induced by cecal ligation and puncture (CLP). Tropisetron hydrochloride (1mg/kg) was administered immediately after surgery. Continuous electrocardiograms were recorded for 5 min before and 1, 2, 4, and 6h after surgery in CLP and sham-operated animals for heart rate variability (HRV) analysis. Blood samples were collected 6h after surgery for serum cytokine and catecholamine assay.
  
  
  RESULTS
  HRV analysis demonstrated a significant increase in LF/(LF+HF) in the CLP animals compared with the sham-operated animals, regardless of tropisetron administration, indicating induction of sympathetic overstimulation. Tropisetron significantly inhibited IL-6 induction in the CLP animals (p<0.01). Although it did not significantly change HRV parameters, tropisetron significantly inhibited increase in serum level of noradrenaline (p<0.05). Tropisetron did not significantly improve CLP animal survival rate.
  
  
  CONCLUSIONS
  Intervention with a 5-HT(3) receptor antagonist can control excess cytokine production involved in the pathogenesis of severe sepsis/septic shock.
authors.affiliation: Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Japan. iki_saikou@hotmail.co.jp
authors.forename: Daisuke
authors.initials: D
authors.lastname: Setoguchi
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Henry
authors.initials: H
authors.lastname: Yatsuki
authors.forename: Eizo
authors.initials: E
authors.lastname: Watanabe
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tateishi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Shigeto
authors.initials: S
authors.lastname: Oda
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D016896:Treatment Outcome; D000077526:Tropisetron
chemical_list: D002395:Catecholamines; D016207:Cytokines; D007211:Indoles; D012702:Serotonin Antagonists; D000077526:Tropisetron