Acute heart failure (AHF) critically affects morbidity and mortality in patients suffering from septic shock. It is hypothesized that AHF is linked to down-regulation of FKBP12.6 (calstabin 2) and SERCA2a (sarco/endoplasmic reticulum Ca2+ ATPase 2a), which may be mediated by an activated endothelin (ET) system in the myocardium. The aim of the study was to test whether an attenuation of septic AHF can be achieved by a novel dual endothelin receptor antagonist, CPU0213, in association with up-regulation of FKBP12.6 and SERCA2a in rats. AHF in septic shock was produced by faeces leak from a surgically punctured caecum for 72 h in rats. CPU0213 (30 mg kg(-1), s.c., every 12 h, for 3 days) was administered to rats 8 h after the operation. In the untreated model group, survival rate markedly decreased (P < 0.01), and the cardiac performance was seriously compromised (P < 0.01) relative to control. The AHF was characteristically associated with down-regulated mRNA and protein expressions of FKBP12.6, SERCA2a and PLB (phospholamban). Elevated ET-1 and mRNA abundances of the preproET-1, ECE (endothelin converting enzyme) and ET(A) and ET(B) receptors in the left ventricular tissue (P < 0.01) were found. All abnormalities were reversed significantly following CPU0213 administration. In conclusion, septic AHF is attributed to down-regulation of FKBP12.6 and SERCA2a, which is related to an activated ET system. An endothelin receptor antagonism of CPU0213 significantly improves the cardiac performance by blocking both ET(A) and ET(B) receptors.