Vol. 298, Issue 3, 1161-1166, September 2001

Lusitropic Effect of MCC-135 Is Associated with Improvement of Sarcoplasmic Reticulum Function in Ventricular Muscles of Rats with Diabetic Cardiomyopathy

Naoya Satoh, Taku Sato, Mayumi Shimada, Kumi Yamada and Yoshimi Kitada

Pharmaceuticals Research Laboratory II, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc., Yokohama, Japan

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 Ca²⁺ uptake, Ca²⁺ release, and Ca²⁺ 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 Ca²⁺ uptake and SR Ca²⁺ release were decreased, and SR Ca²⁺ leakage was increased compared with normal rats. MCC-135 increased SR Ca²⁺ uptake and decreased SR Ca²⁺ leakage in diabetic rats, but not in normal rats. SR Ca²⁺ release was not affected by MCC-135 both in normal and diabetic rats. The combination of protein kinase A and cAMP increased SR Ca²⁺ uptake only in normal rats. These results suggest that MCC-135 has a positive lusitropic effect that might be associated with enhanced Ca²⁺ uptake into the SR and reduced Ca²⁺ leakage from the SR. MCC-135 appears to be more beneficial in treating the failing myocardium with lusitropic abnormality than cAMP-increasing drugs.