Abstract
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.
Footnotes
- Abbreviations:
- SR
- sarcoplasmic reticulum
- [Ca2+]i
- intracellular calcium
- DT
- developed tension
- TTP
- time to peak tension
- TR80
- time to 80% relaxation
- Received March 9, 2001.
- Accepted May 15, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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