Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark.
Department of Cardiovascular Medicine, University of Oxford , Oxford , United Kingdom.
Am J Physiol Heart Circ Physiol. 2018 Jul 1;315(1):H150-H158. doi: 10.1152/ajpheart.00114.2018. Epub 2018 Mar 23.
Remote ischemic conditioning (RIC) protects against sustained myocardial ischemia. Because of overlapping mechanisms, this protection may be altered by glyceryl trinitrate (GTN), which is commonly used in the treatment of patients with chronic ischemic heart disease. We investigated whether long-term GTN treatment modifies the protection by RIC in the rat myocardium and human endothelium. We studied infarct size (IS) in rat hearts subjected to global ischemia-reperfusion (I/R) in vitro and endothelial function in healthy volunteers subjected to I/R of the upper arm. In addition to allocated treatment, rats were coadministered with reactive oxygen species (ROS) or nitric oxide (NO) scavengers. Rats and humans were randomized to 1) control, 2) RIC, 3) GTN, and 4) GTN + RIC. In protocols 3 and 4, rats and humans underwent long-term GTN treatment for 7 consecutive days, applied subcutaneously or 2 h daily transdermally. In rats, RIC and long-term GTN treatment reduced mean IS (18 ± 12%, P = 0.007 and 15 ± 5%, P = 0.002) compared with control (35 ± 13%). RIC and long-term GTN treatment in combination did not reduce IS (29 ± 12%, P = 0.55 vs. control). ROS and NO scavengers both attenuated IS reduction by RIC and long-term GTN treatment. In humans, I/R reduced endothelial function ( P = 0.01 vs. baseline). Separately, RIC and long-term GTN prevented the reduction in endothelial function caused by I/R; given in combination, prevention was lost. RIC and long-term GTN treatment both protect against rat myocardial and human endothelial I/R injury through ROS and NO-dependent mechanisms. However, when given in combination, RIC and long-term GTN treatment fail to confer protection. NEW & NOTEWORTHY Remote ischemic conditioning (RIC) and long-term glyceryl trinitrate (GTN) treatment protect against ischemia-reperfusion injury in both human endothelium and rat myocardium. However, combined application of RIC and long-term GTN treatment abolishes the individual protective effects of RIC and GTN treatment on ischemia-reperfusion injury, suggesting an interaction of clinical importance.
远程缺血预处理（RIC）可预防持续的心肌缺血。由于重叠的机制，这种保护可能会被硝酸甘油（GTN）改变，GTN 通常用于治疗慢性缺血性心脏病患者。我们研究了长期 GTN 治疗是否会改变 RIC 在大鼠心肌和人内皮细胞中的保护作用。我们研究了体外大鼠心脏全缺血再灌注（I/R）时的梗死面积（IS）和健康志愿者手臂 I/R 时的内皮功能。除了分配的治疗外，大鼠还同时给予活性氧（ROS）或一氧化氮（NO）清除剂。大鼠和人随机分为 1）对照组、2）RIC 组、3）GTN 组和 4）GTN+RIC 组。在方案 3 和 4 中，大鼠和人接受了为期 7 天的连续皮下或每天 2 小时的经皮 GTN 治疗。在大鼠中，RIC 和长期 GTN 治疗与对照组（35±13%）相比，降低了平均 IS（18±12%，P=0.007 和 15±5%，P=0.002）。RIC 和长期 GTN 联合治疗并未降低 IS（29±12%，P=0.55 与对照组相比）。ROS 和 NO 清除剂均减弱了 RIC 和长期 GTN 治疗对 IS 的降低作用。在人类中，I/R 降低了内皮功能（P=0.01 与基线相比）。单独的 RIC 和长期 GTN 预防了 I/R 引起的内皮功能降低；联合应用时，预防作用丧失。RIC 和长期 GTN 治疗均通过 ROS 和 NO 依赖性机制保护大鼠心肌和人内皮免受 I/R 损伤。然而，联合应用时，RIC 和长期 GTN 治疗未能提供保护。新的和值得注意的是，远程缺血预处理（RIC）和长期硝酸甘油（GTN）治疗可预防人类内皮和大鼠心肌的缺血再灌注损伤。然而，RIC 和长期 GTN 联合应用消除了 RIC 和 GTN 治疗对缺血再灌注损伤的单独保护作用，表明存在具有临床意义的相互作用。
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