Rösen P, Ballhausen T, Stockklauser K
Department of Clinical Biochemistry, Diabetes Research Institute, Dusseldorf, Germany.
Diabetes Res Clin Pract. 1996 Jul;31 Suppl:S143-55. doi: 10.1016/0168-8227(96)01242-9.
An increased oxidative stress has been suggested to contribute to disturbances in the regulation of coronary flow and the increased cardiac risk in diabetes. Using the isolated perfused heart of streptozotocin-diabetic rats we could recently show [21] that the basal and the maximal coronary flow (tested by infusion of sodium nitroprusside) are not altered in diabetes, but that the 5-HT stimulated endothelial dependent increase in coronary flow becomes progressively impaired. This defect of the endothelium dependent vasodilatation was prevented by perfusion of the hearts with superoxide dismutase and pre-treatment of the diabetic rats with tocopherol-acetate. Perfusion of the hearts with indomethacin to inhibit the synthesis of vasoconstricting prostaglandin endoperoxides did not improve the disturbed 5-HT induced, endothelium dependent increase in coronary flow. Furthermore, acute variations of the glucose concentration in the perfusion medium did not affect the coronary flow significantly. In myocardium, the constitutive endothelial NO synthetase was nearly exclusively expressed with the highest activity in endothelium, as determined from experiments using isolated cardiac endothelial cells. The activity of NO synthetase determined by conversion of arginine to citrulline was significantly increased in diabetes. In line with this observation, the concentration of arginine in plasma was reduced, but that of citrulline elevated. Additionally, the renal elimination of nitrite was enhanced in diabetes. These data suggest that the impaired endothelium dependent relaxation observed in the diabetic myocardium is presumably not caused by a diminished synthesis and release of NO, but by an accelerated inactivation of NO by superoxide anions. We suggest that the increased NO generation reflects a compensatory mechanism to balance the enhanced inactivation of NO.
氧化应激增加被认为与糖尿病患者冠状动脉血流调节紊乱及心脏风险增加有关。最近，我们利用链脲佐菌素诱导的糖尿病大鼠离体灌注心脏模型[21]发现，糖尿病状态下基础和最大冠状动脉血流（通过硝普钠灌注检测）未发生改变，但5-羟色胺刺激的内皮依赖性冠状动脉血流增加逐渐受损。用超氧化物歧化酶灌注心脏以及用醋酸生育酚预处理糖尿病大鼠可预防内皮依赖性血管舒张功能的这一缺陷。用吲哚美辛灌注心脏以抑制血管收缩性前列腺素内过氧化物的合成，并未改善5-羟色胺诱导的、内皮依赖性冠状动脉血流增加的紊乱情况。此外，灌注培养基中葡萄糖浓度的急性变化对冠状动脉血流无显著影响。在心肌中，通过使用分离的心脏内皮细胞进行实验确定，组成型内皮型一氧化氮合酶几乎仅在内皮中以最高活性表达。糖尿病状态下，通过精氨酸向瓜氨酸转化测定的一氧化氮合酶活性显著增加。与此观察结果一致，血浆中精氨酸浓度降低，而瓜氨酸浓度升高。此外，糖尿病患者尿中亚硝酸盐的排泄增加。这些数据表明，糖尿病心肌中观察到的内皮依赖性舒张功能受损可能不是由一氧化氮合成和释放减少所致，而是由超氧阴离子加速一氧化氮失活所致。我们认为，一氧化氮生成增加反映了一种代偿机制，以平衡一氧化氮失活增强的情况。
