Onay-Besikci Arzu, Guner Sahika, Arioglu Ebru, Ozakca Isil, Ozcelikay A Tanju, Altan V Melih
Department of Pharmacology, Faculty of Pharmacy, Ankara University, Tandogan 06100, Ankara, Turkey.
Can J Physiol Pharmacol. 2007 May;85(5):527-35. doi: 10.1139/y07-036.
Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague-Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs-Henseleit solution containing 11 mmol/L glucose, 100 muU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output x heart rate (in (mL/min).(beats/min).10-2), was deteriorated in diabetic (73 +/- 4) and TMZ-treated diabetic (61 +/- 7) groups compared with control (119 +/- 3) and TMZ-treated controls (131 +/- 6). TMZ treatment increased coronary flow in TMZ-treated control (23 +/- 1 mL/min) hearts compared with untreated controls (18 +/- 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 mumol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.
临床和实验证据表明，心肌中脂肪酸氧化速率的增加会导致正常心脏和糖尿病心脏的收缩功能受损。1型糖尿病患者的葡萄糖利用率降低，脂肪酸氧化在能量产生中占主导地位，代价是氧气需求增加。本研究的目的是检查曲美他嗪（TMZ）长期治疗对链脲佐菌素（STZ）诱导的糖尿病大鼠心脏机械功能和脂肪酸氧化的影响。将雄性Sprague-Dawley大鼠的自发跳动心脏在含有11 mmol/L葡萄糖、100 μU/mL胰岛素和0.8 mmol/L与3%牛血清白蛋白（BSA）预结合的棕榈酸的循环Krebs-Henseleit溶液中进行60分钟的有氧灌注。与对照组（119±3）和TMZ治疗的对照组（131±6）相比，糖尿病组（73±4）和TMZ治疗的糖尿病组（61±7）心脏的机械功能（以心输出量×心率表示，单位为（mL/min）·（次/分钟）·10⁻²）恶化。与未治疗的对照组（18±1 mL/min）相比，TMZ治疗增加了TMZ治疗的对照组（23±1 mL/min）心脏的冠状动脉血流量。糖尿病心脏中3-酮酰基辅酶A硫解酶（3-KAT）的mRNA表达增加。在灌注液中棕榈酸浓度为0.8 mmol/L时，未检测到TMZ对脂肪酸氧化的抑制作用。在灌注30分钟时加入1 μmol/L TMZ不影响脂肪酸氧化速率、心脏作功或冠状动脉血流量。我们的结果表明，糖尿病大鼠中3-KAT的较高表达可能需要更高浓度的TMZ才能对脂肪酸氧化产生抑制作用。使用不同浓度脂肪酸对3-KAT进行详细的动力学分析将确定在血浆脂肪酸水平升高的糖尿病状态下TMZ的脂肪酸抑制浓度。
