Xu Z, Patel K P, Rozanski G J
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha 68198-4575, USA.
Am J Physiol. 1996 Nov;271(5 Pt 2):H2190-6. doi: 10.1152/ajpheart.1996.271.5.H2190.
The purpose of this study was to examine the mechanisms of alterations in cardiac K+ channel function in early stages of experimental diabetes mellitus induced by streptozotocin. Transient outward (Ito) and inward rectifier (IK1) K+ currents were recorded by the whole cell voltage-clamp technique in ventricular myocytes isolated from hearts of 2- to 4-wk diabetic and age-matched control rats. Ito density in myocytes from diabetic rats was approximately 30% less than control (at +60 mV; P < 0.01) under basal recording conditions in the presence of 18 mM external glucose, whereas IK1 density was not different between groups. When external glucose concentration was decreased to 5 mM for 4-6 h, basal Ito density was not changed in either group of myocytes. To further examine the possible metabolic basis of reduced Ito density in myocytes from diabetic rats, we separately tested three structurally different compounds that affect substrate utilization in cardiac myocytes: insulin (0.1 microM), dichloroacetate (1.5 mM), and L-carnitine (10 mM). Each compound completely normalized Ito density in myocytes from diabetic rats treated in vitro for 4-6 h. The same agents had no effect on Ito density in control myocytes, nor was IK1 altered in either group of cells. These data provide the first evidence to support the hypothesis that there is a metabolic basis for decreased Ito density in diabetic rat ventricular myocytes in early stages of this model. Furthermore, our data suggest that depressed glucose metabolism in the diabetic heart may be a key factor underlying changes in Ito channel function, because agents that increase glucose utilization normalize Ito density within a short time period.
本研究的目的是探讨链脲佐菌素诱导的实验性糖尿病早期心脏钾通道功能改变的机制。采用全细胞电压钳技术，记录从2至4周龄糖尿病大鼠和年龄匹配的对照大鼠心脏分离的心室肌细胞中的瞬时外向钾电流（Ito）和内向整流钾电流（IK1）。在存在18 mM外源性葡萄糖的基础记录条件下，糖尿病大鼠心肌细胞中的Ito密度比对照组低约30%（在+60 mV时；P<0.01），而两组之间的IK1密度没有差异。当外源性葡萄糖浓度降低至5 mM持续4至6小时时，两组心肌细胞的基础Ito密度均未改变。为了进一步研究糖尿病大鼠心肌细胞中Ito密度降低的可能代谢基础，我们分别测试了三种结构不同的影响心肌细胞底物利用的化合物：胰岛素（0.1 microM）、二氯乙酸盐（1.5 mM）和L-肉碱（10 mM）。每种化合物都能使体外处理4至6小时的糖尿病大鼠心肌细胞中的Ito密度完全恢复正常。相同的药物对对照心肌细胞中的Ito密度没有影响，两组细胞中的IK1也未改变。这些数据提供了首个证据支持这一假说，即在该模型早期，糖尿病大鼠心室肌细胞中Ito密度降低存在代谢基础。此外，我们的数据表明，糖尿病心脏中葡萄糖代谢降低可能是Ito通道功能改变的关键因素，因为增加葡萄糖利用的药物能在短时间内使Ito密度恢复正常。
