Abstract:
Objective: This study examines the extent to which the contractile deficit of diabetic cardiomyopathy is due to altered calcium metabolism. Methods: Measurements of isometric force and intracellular calcium ([Ca2+]i, fura-2/AM) were made in left ventricular trabeculae from streptozotocin (STZ)-induced diabetic rats and age-matched siblings. Results: At 1.5 mmol/L [Ca2+]o, 37 °C, and 5 Hz stimulation frequency, peak stress was depressed in diabetic rats (10 ±1 mN/mm2 vs 17 ±2 mN/mm2 control, P<0.05) with a slower time-to-peak stress (0.077 ±0.003s vs. 0.067 ±0.002s control, P<0.01) and time-to-90% relaxation (0.076 ±0.007s vs; 0.056 ±0.003s control, P<0.05). No difference was found between groups for either resting or peak Ca2+, but the Ca2+ transient was slower in time-to-peak (0.039 ±0.002s vs. 0.034 ±0.001s control) and decayed more slowly (time constant, 0.061 ±0.003s vs 0.049 ±0.003s control). Diabetic rats had a longer LV action potential (APD50, 0.098 ±0.005s vs. 0.062 ±0.005s control, P<0.0001). Western blotting showed that diabetic rats had a reduced expression of SERCA2a, with no difference in expression of the Na+/Ca2+-exchanger. Immunohistochemistry of LV free wall showed type I collagen was increased in diabetic rats (Diabetic: 7.1 ±0.1%; Control: 12.7 ±0.1%, P<0.01), and f-actin content reduced (Diabetic: 56.9 ±0.6%; Control: 61.7 ±0.4%, P<0.0001) with a disrupted structure. Conclusion: We find no evidence to support the idea that altered Ca2+ metabolism underlies the contractile deficit of diabetic cardiomyopathy. The slower action potential and reduced SERCA2a expression can explain the slower Ca2+ transient kinetics in diabetic rats, but not the contractile deficit. Instead, we suggest that the observed LV remodeling may play a crucial role.
