Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Nagyvárad tér 4, P.O.B. 370, 1445, Hungary.
Curr Med Chem. 2011;18(24):3720-8. doi: 10.2174/092986711796642364.
Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 µM) shortened AP duration at 90% level of repolarization (APD(90)) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 µM) caused a significant reduction of APA and maximum velocity of depolarization (V(max)) which was accompanied by lengthening of APD(90). In single canine ventricular myocytes at concentrations ≥10 µM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced V(max). R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC(50) value for this inhibition was 25.2±2.7 µM for the transient outward K(+ ) current (I(to)), 72.3±9.3 µM for the rapid delayed rectifier K(+ ) current (I(Kr)), and 82.5±9.4 µM for the L-type Ca(2+ ) current (I(Ca)) with Hill coefficients close to unity. The inward rectifier K(+ ) current (I(K1)) was not affected by R up to concentrations of 100 µM. Suppression of I(to), I(Kr), and I(Ca) has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.
最近的大型临床试验发现，抗糖尿病药物罗格列酮治疗与心血管不良事件风险增加之间存在关联。本报告的目的是使用常规微电极、全细胞膜片钳和动作电位（AP）电压钳技术，阐明罗格列酮（R）对分离的大鼠和小鼠心室乳头状肌细胞以及犬心室肌细胞的心脏电生理特性。在组氨酸脱羧酶敲除小鼠及其野生型中，R（1-30 µM）浓度依赖性地缩短了复极化 90%水平的动作电位时程（APD90）并增加了动作电位幅度（APA）。在大鼠心室乳头状肌细胞中，R（1-30 µM）导致 APA 和最大去极化速度（Vmax）显著降低，同时 APD90 延长。在浓度≥10 µM 的单个犬心室肌细胞中，R 降低了 1 相复极化幅度、平台电位并降低了 Vmax。R 在电压钳条件下以浓度依赖性方式抑制几种离子电流。这种抑制的 EC50 值为 25.2±2.7 µM 用于瞬时外向 K+（Ito）电流，72.3±9.3 µM 用于快速延迟整流 K+（IKr）电流，82.5±9.4 µM 用于 L 型 Ca2+（ICa）电流，其希尔系数接近 1。R 直至 100 µM 浓度均未影响内向整流 K+（IK1）电流。在动作电位电压钳条件下也证实了 Ito、IKr 和 ICa 的抑制作用。AP 形态和离子电流密度的改变可能预示着 R 中毒时会出现严重的致心律失常风险，尤其是在有多种心血管危险因素的患者中，例如老年糖尿病患者。
