Alterations of heart function and Na+-K+-ATPase activity by etomoxir in diabetic rats

To examine the role of changes in myocardial metabolism in cardiac dysfunct ion 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 i n heart rate, left ventricular systolic pressure, and positive and negative rate of pressure development and an increase in end-diastolic pressure. Th e sarcolemmal Na+-K+-ATPase activity was depressed and was associated with a decrease in maximal density of binding sites (B-max) value for high-affin ity sites for [H-3]ouabain, whereas B-max for low-affinity sites was unaffe cted. Treatment of diabetic animals with etomoxir partially reversed the de pressed cardiac function with the exception of heart rate. The high serum t riglyceride and free fatty acid levels were reduced, whereas the levels of glucose, insulin, and 3,3',-5-triiodo-L-thyronine were not affected by etom oxir in diabetic animals. The activity of Na+-K+-ATPase expressed per gram heart weight, but not per milligram sarcolemmal protein, was increased by e tomoxir in diabetic animals. Furthermore, B-max (per g heart wt) for both l ow-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 increas e the density of the sarcolemma and transverse tubular system to normalize Na+-K+-ATPase activity. Therefore, a shift, in myocardial substrate utiliza tion may represent an important signal for improving the depressed cardiac function and Na+-K+-ATPase activity in diabetic rat hearts with impaired gl ucose utilization.