Effects of
MCC-135 on contraction and relaxation properties and sarcoplasmic reticulum (SR) function were investigated in the failing ventricular muscle due to
diabetic cardiomyopathy. Wistar rats were made diabetic by a single injection of
streptozotocin (40 mg/kg i.v.). Seven months later, the left ventricular papillary muscle was isolated and isometric tension was measured. The skinned fiber with functional SR preserved was prepared by treatment of the papillary muscle with
saponin and used to study SR Ca(2+) uptake, Ca(2+) release, and Ca(2+) leakage. In diabetic rats, developed tension (DT) was decreased, and 80% relaxation time (TR80) and time to peak tension (
TTP) were increased compared with normal rats.
MCC-135 decreased TR80 and
TTP without significant effect on DT in diabetic rats, but not in normal rats.
Isoproterenol increased DT, and decreased
TTP and TR80 only in normal rats. In diabetic rats, SR Ca(2+) uptake and SR Ca(2+) release were decreased, and SR Ca(2+) leakage was increased compared with normal rats.
MCC-135 increased SR Ca(2+) uptake and decreased SR Ca(2+) leakage in diabetic rats, but not in normal rats. SR Ca(2+) release was not affected by
MCC-135 both in normal and diabetic rats. The combination of
protein kinase A and cAMP increased SR Ca(2+) uptake only in normal rats. These results suggest that
MCC-135 has a positive lusitropic effect that might be associated with enhanced Ca(2+) uptake into the SR and reduced Ca(2+) leakage from the SR.
MCC-135 appears to be more beneficial in treating the failing myocardium with lusitropic abnormality than cAMP-increasing drugs.