Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
J Cardiovasc Pharmacol Ther. 2012 Jun;17(2):181-9. doi: 10.1177/1074248411416118. Epub 2011 Aug 9.
The interaction of diabetes with cardioprotection by postconditioning in ischemia/reperfusion injury remains unclear. The aim of this study was to investigate the concomitant effects of ischemic postconditioning (IPostC) and cyclosporine-A (CsA) on nitric oxide (NO) content and parameters of cardiac function of the diabetic myocardium injured by ischemia/reperfusion.
Diabetes was induced by single injection of streptozotocin (50 mg/kg; intraperitoneally [ip]) in Wistar rats (250-320 g) and the diabetic period was 8 weeks. The hearts (n = 96) were removed quickly, mounted on Langendorff apparatus, and then subjected to 30-minute regional ischemia followed by 45-minute reperfusion. Ischemic postconditioning was induced by 3 cycles of 30-second reperfusion/ischemia at the onset of reperfusion. Myocardial function was measured throughout the experiment, and infarct size (IS) was identified by triphenyltetrazolium chloride (TTC) staining. Total amounts of NO metabolites were determined using Griess method and enzyme-linked immunosorbent assay (ELISA) reader.
Administration of either IPostC or CsA alone in nondiabetic animals significantly improved myocardial function and reduced the ISs (28% ± 1.9% or 23% ± 2.0% vs 41% ± 2.9% of the risk zone [RZ], respectively; P < .01), but they had no effect on diabetic hearts (35% ± 1.8% or 32% ± 2.1% vs 39% ± 3.1%, respectively). In addition, myocardial NO level was significantly increased by IPostC only in nondiabetic animals (P < .01). However, after administration of CsA (5 minutes before and 10 minutes after the onset of reperfusion) in postconditioned animals, the cardioprotective and NO-enhancing effects of IPostC were restored in diabetic rats (IS: 21% ± 1.1% vs 39% ± 3.1%), similar to those in nondiabetic controls (19% ± 1.3% vs 41% ± 2.9%; P < .01).
The present study indicated that IPostC or CsA failed to affect NO levels and failed to protect the diabetic myocardium against ischemia/reperfusion injury. Moreover, concomitant administration of CsA and IPostC at reperfusion can increase NO content and protect the diabetic myocardium.
糖尿病与缺血/再灌注损伤中后处理的心脏保护之间的相互作用尚不清楚。本研究旨在探讨缺血后处理（IPostC）和环孢素 A（CsA）联合应用对缺血/再灌注损伤的糖尿病心肌的一氧化氮（NO）含量和心功能参数的影响。
Wistar 大鼠（250-320g）单次腹腔注射链脲佐菌素（50mg/kg）诱导糖尿病，糖尿病持续 8 周。取出心脏（n=96），迅速安装在 Langendorff 装置上，然后进行 30 分钟的局部缺血，再进行 45 分钟的再灌注。再灌注开始时，通过 3 个 30 秒的再灌注/缺血循环诱导缺血后处理。整个实验过程中测量心肌功能，用三苯基四唑氯（TTC）染色确定梗死面积（IS）。用格里斯法和酶联免疫吸附试验（ELISA）读取器测定总 NO 代谢产物的量。
单独给予 IPostC 或 CsA 均可显著改善非糖尿病动物的心肌功能并减少梗死面积（分别为 28%±1.9%或 23%±2.0%与 41%±2.9%的风险区[RZ]，P<0.01），但对糖尿病心脏无影响（分别为 35%±1.8%或 32%±2.1%）。此外，只有在非糖尿病动物中，IPostC 可显著增加心肌 NO 水平（P<0.01）。然而，在再灌注开始前 5 分钟和再灌注开始后 10 分钟给予 CsA 后，糖尿病大鼠的 IPostC 的心脏保护和增强 NO 作用得到恢复（IS：21%±1.1%与 39%±3.1%），与非糖尿病对照组相似（19%±1.3%与 41%±2.9%；P<0.01）。
本研究表明，IPostC 或 CsA 不能影响 NO 水平，不能保护糖尿病心肌免受缺血/再灌注损伤。此外，再灌注时同时给予 CsA 和 IPostC 可增加 NO 含量并保护糖尿病心肌。
