The depressed sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) and Ca2+-release 
channels (ryanodine receptor RyR2) are involved in the diabetic cardiomyopathy. 
However, an implication of a down-regulation of FK506-binding protein or 
calstabin-2 (FKBP12.6) is undefined. It was hypothesized that the 
down-regulation of FKBP12.6 and SERCA2a of the intracellular calcium handling 
system is closely related to an up-regulated endothelin (ET) system. An ET 
receptor antagonist CPU0213 is newly discovered and expected to ameliorate 
cardiac insufficiency which is mediated by the depressed FKBP12.6 and SERCA2a in 
diabetic rat heart. Diabetes was developed in male Sprague-Dawley rats 8 weeks 
after an injection of streptozotocin (60 mg/kg IP), and CPU0213 was instituted 
30 mg/kg, SC in the last 4 weeks. The assessment of the cardiac function, 
cardiac calcium handling proteins, endothelin system, and redox enzyme system 
were conducted. The compromised cardiac function in diabetic rats was 
accompanied by a significant down-regulation of expression of FKBP12.6 as well 
as SERCA2a and phospholamban. These were closely linked with an increased ET-1 
and up-regulation of endothelin converting enzyme, PropreET1, and inducible 
nitric oxide synthase mRNA in diabetic cardiomyopathy. After 4-week treatment, 
CPU0213 was capable to attenuate completely the down-regulated FKBP12.6 and 
SERCA2a, and up-regulated ET system in association with a recovery of the 
cardiac insufficiency of diabetic cardiomyopathy.