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.