Aim:The downregutation of phospholamban (PLB) and FKBP12.6 as a result of β-receptor activation is involved in the pathway(s) of congestive heart failure.Wehypothesized that the endothelin (ET)-1 system may link to downregulated PLBand FKBP12.6.Methods:Rats were subjected to ischemia/reperfusion (I/R) tocause heart failure (HF).1 mg/kg isoproterenol (ISO) was injected subcutane-ously (sc) for 10 d to worsen HF.30 mg/kg CPU0213 (sc),a dual ET receptor.(ET_AR/ET_BR) antagonist was given from d 6 to d 10.On d 11,cardiac function wasassessed together with the determination of mRNA levels of ryanodine receptor 2,calstabin-2 (FKBP12.6),PLB,and sarcoplasmic reticulum Ca~(2+)-ATPase.Isolatedadult rat ventricular myocytes were incubated with ISO at 1×10~(-6) mol/L to set up anin vitro model of HF.Propranolol (PRO),CPU0213,and darusentan (DAR,anET_AR antagonist) were incubated with cardiomyocytes at 1×10~(-5) mol/L or 1×10~(-6)mol/L in the presence of ISO (1×10~(-6) mol/L).Immunocytochemistry and Westernblotting were applied for measuring the protein levels of PLB and FKBP12.6.Results:The worsened hemodynamics produced by I/R were exacerbated by ISOpretreatment.The significant downregulation of the gene expression of PLB andFKBP12.6 and worsened cardiac function by ISO were reversed by CPU0213.Invitro ISO 1×10~(-6) mol/L produced a sharp decline of PLB and FKBP12.6 proteinsrelative to the control.The downregulation of the protein expression was signifi-cantly reversed by the ET receptor antagonist CPU0213 or DAR,comparable tothat achieved by PRO.Conclusion:This study demonstrates a role of ET inmediating the downregulation of the cardiac Ca~(2+)-handling protein by ISO. Aim: The downregation of phospholamban (PLB) and FKBP12.6 as a result of β-receptor activation is involved in the pathway (s) of congestive heart failure. We hypothesized that the endothelin (ET) -1 system may link to downregulated PLBand FKBP12 .6 Methods: Rats were subjected to ischemia / reperfusion (I / R) tocause heart failure (HF) .1 mg / kg isoproterenol (ISO) was injected subcutaneously ously (sc) The CPU0213 (sc), a dual ET receptor. (ET_AR / ET_BR) antagonist was given from d 6 to d 10. On d 11, cardiac function was assessed together with the determination of mRNA levels of ryanodine receptor 2, calstabin-2 (FKBP12 .6), PLB, and sarcoplasmic reticulum Ca ~ (2 +) - ATPase.Isolatedadult rat ventricular myocytes were incubated with ISO at 1 × 10 ~ (-6) mol / L to set up anin vitro model of HF.Propranolol ), CPU0213, and darusentan (DAR, anET_AR antagonist) were incubated with cardiomyocytes at 1 × 10 -5 mol / L or 1 × 10 -6 mol / L in the presence of ISO at 1 × 10 ~ (-6) mol / L) .Immunocytochemist ry and Western blotting were applied for measuring the protein levels of PLB and FKBP 12.6. Results: The worsened hemodynamics produced by I / R were exacerbated by ISO pretreatment. significant gene regulation of the gene expression of PLB and FKBP12.6 and worsened cardiac function by ISO Resolved by the CPU0213. Invitro ISO 1 × 10 -6 mol / L produced a sharp decline of PLB and FKBP12.6 proteinsrelative to the control. The downregulation of the protein expression was signifi-cantzed by the ET receptor antagonist CPU0213 or DAR, comparable tothat achieved by PRO.Conclusion: This study demonstrates a role of ET in mediating the downregulation of the cardiac Ca ~ (2 +) - handling protein by ISO.