Objective: Aim of this study was to elucidate, whether in vivo application of the Toll-like- Receptor 4 (TLR4) antagonist Eritoran prevents lipopolysaccharide (LPS) induced hypotension, cardiac failure, loss of vascular resistance and cytokine production in the murine heart. Methods: 12-14 week old C3H/HeN mice were treated with either 2 mg/kg bodyweight (BW) LPS or 4 mg/kgBW Eritoran + 2 mg/kgBW LPS, LPS injected i.p. and Eritoran tetrasodium (Esai Inc., Endover, MA USA) injected i.v. 6 h later, hemodynamic parameters and vascular response were measured in vivo by Millar catheter. In addition, blood pressure was recorded previous to and after LPS as well as LPS and Eritoran tetrasodium injection by Physiotel telemetry catheters. After 2 and 6 hours of stimulation hearts and aortae were explanted and cytokine expressions measured using real-time PCR and ELISA. Results: LPS treatment led to depression of hemodynamic parameters, being significantly smaller in the Eritoran tetrasodium group. 2 h of LPS stimulation led to a significant increase of pro- and anti-inflammatory cytokine mRNA (TNF-a, IL-1b, IL-6, IL-10) in hearts and aortae, approaching baseline levels after 6 h. Combined injection of LPS and Eritoran tetrasodium also increased cytokine levels in hearts and aortae. But in the aortae cytokine mRNA expression was reduced compared to LPS alone. LPS increased iNOS mRNA expression highly in both organs after 6 h and this was decreased significantly by Eritoran. Conclusion: The TLR-4 antagonist Eritoran tetrasodium reduces LPS induced cardiac depression. This appears to be mainly due to inhibition of iNOS expression in hearts and aortae. Thus pharmacological intervention with Eritoran tetrasodium may be a new opportunity to stabilize the circulation during endotoxemia.