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Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6
To examine the
role of changes in myocardial metabolism in cardiac dysfunction in
diabetes mellitus, rats were injected with streptozotocin (65 mg/kg
body wt) to induce diabetes and were treated 2 wk later with the
carnitine palmitoyltransferase inhibitor (carnitine
palmitoyltransferase I) etomoxir (8 mg/kg body wt) for 4 wk. Untreated
diabetic rats exhibited a reduction in heart rate, left ventricular
systolic pressure, and positive and negative rate of pressure
development and an increase in end-diastolic pressure. The sarcolemmal
Na+-K+-ATPase
activity was depressed and was associated with a decrease in maximal
density of binding sites (Bmax)
value for high-affinity sites for
[3H]ouabain, whereas
Bmax for low-affinity sites was
unaffected. Treatment of diabetic animals with etomoxir
partially reversed the depressed cardiac function with the exception of
heart rate. The high serum triglyceride and free fatty acid levels were
reduced, whereas the levels of glucose, insulin, and
3,3',-5-triiodo-L-thyronine were not affected by etomoxir in diabetic animals. The activity of
Na+-K+-ATPase
expressed per gram heart weight, but not per milligram sarcolemmal
protein, was increased by etomoxir in diabetic animals. Furthermore,
Bmax (per g heart wt) for both
low-affinity and high-affinity binding sites in control and diabetic
animals was increased by etomoxir treatment. Etomoxir treatment also
increased the depressed left ventricular weight of diabetic rats and
appeared to increase the density of the sarcolemma and transverse
tubular system to normalize
Na+-K+-ATPase
activity. Therefore, a shift in myocardial substrate utilization may
represent an important signal for improving the depressed cardiac
function and
Na+-K+-ATPase
activity in diabetic rat hearts with impaired glucose utilization.
diabetic heart; etomoxir; carnitine palmitoyltransferase I; sarcolemmal sodium-potassium-3',5'-adenosine triphosphatase; heart dysfunction in diabetes
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