MODIFICATION OF MYOSIN ISOZYMES AND SR CA2-PUMP ATPASE OF THE DIABETIC RAT-HEART BY LIPID-LOWERING INTERVENTIONS()

To define metabolic influences on cardiac myosin expression and sarcop lasmic reticulum (SR) Ca2+-stimulated ATPase, streptozotocin-diabetic rats were treated for 9-10 wk with etomoxir, an inhibitor of carnitine palmitoyl transferase I (CPT-1) and fatty acid synthesis, or an antil ipolytic drug, acipimox. Etomoxir reduced myosin V-3 of diabetic rats but did not normalize it. However, the high serum triglyceride, free-f atty acid and cholesterol concentrations in diabetic animals were grea tly reduced. After bypassing the CPT-1 inhibition with a medium-chain fatty acid (miglyol) diet, the V-3 contents and serum lipids were stil l reduced in the etomoxir-treated diabetic rats; V-3 was also reduced in diabetic rats fed miglyol or treated with acipimox. Since low serum insulin or triiodothyronine concentrations in diabetic rats were not improved by these interventions but changes in V-3 were correlated wit h those in triglyceride, free-fatty acid and cholesterol concentration s, it is likely that myosin may be influenced by some metabolic factor s. To assess the role of adrenergic influences, diabetic rats (7-8 wk) were treated with an antisympathotonic drug, moxonidine, a beta-adren oceptor blocking drug, propranolol, and a bradycardic drug, tedisamil. Myosin V-3 was not reduced significantly in moxonidine-treated or pro pranolol-treated rats in comparison to untreated diabetic rats. Serum thyroid hormones and insulin were not altered, whereas triglycerides w ere reduced but not significantly by these antiadrenergic agents. Lowe ring serum lipids in diabetic rats by treatment with etomoxir, miglyol and acipimox increased the depressed SR Ca2+ stimulated ATPase activi ty. On the other hand, in diabetic rats treated with moxonidine, propr anolol or tedisamil, the ATPase activity was not increased significant ly. These results suggest that normalization of blood lipids is import ant for improving subcellular organelle function in diabetic hearts wi th impaired glucose utilization.