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Mechanisms of alpha1-adrenoceptor mediated QT prolongation in the diabetic rat heart.

机译：糖尿病大鼠心脏中α1-肾上腺素受体介导的QT延长的机制。

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AIMS: Diabetes mellitus is associated with changes of alpha(1)-adrenoceptor (alpha(1)-AR) on heart electrical function and expression. In this study, we investigated the ionic basis underlying abnormal alpha(1)-AR mediated QT prolongation in the diabetic rat hearts. MAIN METHODS: Electrophysiological and biochemical techniques were used in Streptozotocin (STZ)-induced diabetic and control rat hearts. KEY FINDINGS: In both control and diabetic rats, the alpha(1)-AR agonist, phenylephrine (PE, 10-100 microM) prolonged the rate-corrected QT intervals (QTc) and action potential durations at 30% (APD(30)) and 90% (APD(90)) repolarization levels with the increased QTc and APD(90) significantly greater in diabetic rats. PE significantly decreased the transient outward K(+) current (I(to)) and the steady-state K(+) current (I(ss)) in both control and diabetic rats but had no effects on the delayed rectifier K(+) current (I(k)). However, PE induced a greater reduction mainly in the I(ss), but not I(to), in diabetic rats. Furthermore, using RT-PCR and Western blot analyses, we found that alpha(1A)-ARs were over-expressed in the left ventricular tissues of the diabetic rat hearts at both the mRNA and the protein levels. SIGNIFICANCE: These data suggested that in diabetic hearts, a greater sensitivity of the alpha(1A)-AR mediated the larger suppression of I(ss) and resulted in a more prolonged APD(90) and QTc. Thus, higher alpha(1A)-AR expression levels in diabetic heart may underlie this type of diabetic cardiomyopathy and suggests that alpha(1A)-AR may serve as a therapeutic target.
机译：目的：糖尿病与α（1）-肾上腺素能受体（alpha（1）-AR）在心脏电功能和表达上的变化有关。在这项研究中，我们调查了糖尿病大鼠心脏中异常α（1）-AR介导的QT延长的离子基础。主要方法：电生理和生化技术被用于链脲佐菌素（STZ）诱导的糖尿病和对照大鼠心脏。主要发现：在对照组和糖尿病大鼠中，α（1）-AR激动剂去氧肾上腺素（PE，10-100 microM）均将速率校正的QT间隔（QTc）和动作电位持续时间延长了30％（APD（30）） ）和90％（APD（90））的复极水平随着QTc和APD（90）的增加而明显增加。 PE显着降低了对照组和糖尿病大鼠的瞬时向外K（+）电流（I（to））和稳态K（+）电流（I（ss）），但对延迟整流器K（+）没有影响）电流（I（k））。然而，PE诱导的减少主要在糖尿病大鼠的I（ss）而非I（to）上。此外，使用RT-PCR和Western印迹分析，我们发现在糖尿病大鼠心脏的左心室组织中，无论是mRNA还是蛋白水平，α（1A）-ARs均过表达。意义：这些数据表明，在糖尿病心脏中，较高的α（1A）-AR敏感性介导了对I（ss）的更大抑制，并导致更长的APD（90）和QTc。因此，糖尿病心脏中较高的α（1A）-AR表达水平可能是这种类型的糖尿病性心肌病的基础，并暗示α（1A）-AR可以作为治疗靶标。

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