Ren J, Dominguez L J, Sowers J R, Davidoff A J
Program in Molecular and Cellular Cardiology, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Diabetes. 1996 Dec;45(12):1822-5. doi: 10.2337/diab.45.12.1822.
Diabetes is associated with impaired cardiac diastolic dysfunction. Isolated ventricular myocytes from diabetic animals demonstrate impaired relaxation concomitant with prolonged intracellular Ca2+ transients. We have recently shown that maintaining normal adult rat ventricular myocytes in a "diabetic-like" culture medium (low insulin and high glucose) produces abnormalities in excitation-contraction coupling similar to in vivo diabetes. Troglitazone (TRO), a novel insulin-sensitizing agent, significantly lowers blood pressure and modestly increases cardiac output in vivo, but its direct impact on cardiac function is unknown. To determine whether TRO could prevent high-glucose-induced dysfunction, normal myocytes were maintained in culture for 1-2 days in either normal medium containing 5 mmol/l glucose or high-glucose medium containing 25 mmol/l glucose. TRO (5 micromol/l) was added to both normal and high-glucose media. Mechanical properties were evaluated using a high-resolution video-edge detection system, and Ca2+ transients were recorded in fura-2-loaded myocytes. Relaxation from peak contraction was significantly longer in myocytes cultured in high glucose. Treating cells with TRO either attenuated or prevented the high-glucose effects, without changing the mechanical properties of myocytes cultured in normal medium. TRO also prevented the abnormally slow rates of Ca2+ transient decay induced by high glucose. Collectively, these data demonstrate that TRO can protect against the high-glucose-induced relaxation defects, perhaps through changes in intracellular Ca2+ handling. If TRO has both vasodilatory actions and beneficial cardiac properties (e.g., improvement of diastolic function) in the presence of hyperglycemia, this antidiabetic agent may prove to have significant salutary cardiovascular effects in type II diabetes.
糖尿病与心脏舒张功能障碍有关。来自糖尿病动物的孤立心室肌细胞表现出舒张受损，伴有细胞内Ca2+瞬变延长。我们最近发现，将正常成年大鼠心室肌细胞置于“糖尿病样”培养基（低胰岛素和高葡萄糖）中会产生与体内糖尿病相似的兴奋-收缩偶联异常。曲格列酮（TRO）是一种新型胰岛素增敏剂，在体内可显著降低血压并适度增加心输出量，但其对心脏功能的直接影响尚不清楚。为了确定TRO是否能预防高糖诱导的功能障碍，将正常心肌细胞在含有5 mmol/l葡萄糖的正常培养基或含有25 mmol/l葡萄糖的高糖培养基中培养1-2天。TRO（5 μmol/l）添加到正常培养基和高糖培养基中。使用高分辨率视频边缘检测系统评估机械性能，并在加载fura-2的心肌细胞中记录Ca2+瞬变。在高糖培养基中培养的心肌细胞从峰值收缩开始的舒张明显更长。用TRO处理细胞可减轻或预防高糖效应，而不改变在正常培养基中培养的心肌细胞的机械性能。TRO还可预防高糖诱导的Ca2+瞬变异常缓慢的衰减率。总体而言，这些数据表明TRO可能通过改变细胞内Ca2+处理来保护心肌细胞免受高糖诱导的舒张缺陷。如果TRO在高血糖情况下同时具有血管舒张作用和有益的心脏特性（如改善舒张功能），那么这种抗糖尿病药物可能在II型糖尿病中具有显著的心血管益处。
