Nicholl T A, Lopaschuk G D, McNeill J H
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Am J Physiol. 1991 Oct;261(4 Pt 2):H1053-9. doi: 10.1152/ajpheart.1991.261.4.H1053.
It is well established that cardiac dysfunction independent of atherosclerosis develops in both humans and animals with diabetes mellitus. The etiology is complex, involving many different processes, one of which may be increased fatty acid utilization and/or a concomitant decrease in glucose utilization by the diabetic heart. We compared control and 6-wk streptozotocin (STZ)-induced diabetic isolated working rat hearts and were able to demonstrate cardiac dysfunction in the diabetic as assessed by depressed heart rate (HR), heart rate peak systolic pressure product (HR.PSP), left ventricular developed pressure (LVDP), and rate of pressure rise (+dP/dt). Paralleling depressed cardiac function in the diabetic were hyperglycemia, hyperlipidemia, and decreased body weight gain compared with age-matched controls. The addition of free fatty acids, in the form of 1.2 mM palmitate, to the isolated working heart perfusate had no effect on either control or diabetic heart function, with the exception of a depressive effect on +dP/dt of diabetic hearts. But diabetic hearts perfused with palmitate-containing perfusate plus the glucose oxidation stimulator dichloroacetate (DCA) showed a marked improvement in function. HR and HR.PSP in spontaneously beating hearts, as well as LVDP and +dP/dt in paced hearts were all restored to control heart values in diabetic hearts perfused in the presence of DCA. Creatine phosphate and ATP levels were similar under all perfusion conditions, thus eliminating energy stores as the limiting factor in heart function. Results indicate that DCA will acutely reverse diabetic cardiac function depression. Therefore glucose oxidation depression in the diabetic heart may be a significant factor contributing to cardiac dysfunction.
众所周知，糖尿病患者（包括人类和动物）会出现与动脉粥样硬化无关的心脏功能障碍。其病因复杂，涉及许多不同过程，其中之一可能是糖尿病心脏脂肪酸利用增加和/或葡萄糖利用相应减少。我们比较了对照大鼠和经6周链脲佐菌素（STZ）诱导的糖尿病大鼠的离体工作心脏，发现糖尿病心脏存在心脏功能障碍，表现为心率（HR）、心率-收缩压峰值乘积（HR.PSP）、左心室舒张末压（LVDP）和压力上升速率（+dP/dt）降低。与年龄匹配的对照组相比，糖尿病患者心脏功能下降的同时伴有高血糖、高血脂和体重增加减少。向离体工作心脏灌注液中添加1.2 mM棕榈酸形式的游离脂肪酸，除了对糖尿病心脏的 +dP/dt有抑制作用外，对对照心脏或糖尿病心脏功能均无影响。但是，用含棕榈酸的灌注液加葡萄糖氧化刺激剂二氯乙酸（DCA）灌注的糖尿病心脏功能有显著改善。在有DCA存在的情况下灌注的糖尿病心脏中，自发搏动心脏的HR和HR.PSP以及起搏心脏的LVDP和 +dP/dt均恢复到对照心脏水平。在所有灌注条件下，磷酸肌酸和ATP水平相似，因此排除了能量储备作为心脏功能限制因素的可能性。结果表明，DCA可急性逆转糖尿病心脏功能抑制。因此，糖尿病心脏中葡萄糖氧化抑制可能是导致心脏功能障碍的一个重要因素。
