Abstract

OBJECTIVE—This study examines the extent to which the contractile deficit of diabetic cardiomyopathy is due to altered Ca²⁺ homeostasis.

RESEARCH DESIGN AND METHODS—Measurements of isometric force and intracellular calcium ([Ca²⁺]_i, using fura-2/AM) were made in left ventricular (LV) trabeculae from rats with streptozotocin-induced diabetes 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 vs. 17 ± 2 mN/mm² in controls; P < 0.05) with a slower time to peak stress (77 ± 3 vs. 67 ± 2 ms; P < 0.01) and time to 90% relaxation (76 ± 7 vs. 56 ± 3 ms; 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 (39 ± 2 vs. 34 ± 1 ms) and decay (time constant, 61 ± 3 vs. 49 ± 3 ms). Diabetic rats had a longer LV action potential (APD₅₀, 98 ± 5 vs. 62 ± 5 ms; P < 0.0001). Western blotting showed that diabetic rats had a reduced expression of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a, with no difference in expression of the Na⁺/Ca²⁺ exchanger. Immunohistochemistry of LV free wall showed that 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.

CONCLUSIONS—We find no evidence to support the idea that altered Ca²⁺ homeostasis 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.