Department for Angiology, Brandenburg Medical School, Campus Brandenburg/Havel, Brandenburg/Havel, Germany.
Department of Cardiology, Charité University Hospital, Campus Virchow, Berlin, Germany.
PLoS One. 2018 Aug 17;13(8):e0201597. doi: 10.1371/journal.pone.0201597. eCollection 2018.
In the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats.
Coronary collateral growth was induced via a repetitive occlusion protocol (ROP) of the left anterior descending coronary artery (LAD) in rats. The primary endpoints were the histological evaluation of rat heart infarct size and ST-segment elevation (ECG-analysis) upon final permanent occlusion of the LAD (experimentally induced myocardial infarction). The effects of NTG or ISDN were also evaluated by administration during 5 days of ROP. We additionally investigated whether concomitant application of NTG can compensate for the anti-arteriogenic effect of acetylsalicylic acid (ASA).
After 5 days of ROP, the mean infarct size and degree of ST-elevation were only slightly lower than those of the SHAM group; however, after 10 days of the protocol, the ROP group displayed significantly less severe infarct damage, indicating enhanced arteriogenesis. Intermittent NTG application greatly decreased the ST-elevation and infarct size. The ISDN also had a positive effect on arteriogenesis, but not to the same extent as the NTG. Administration of ASA increased the infarct severity; however, concomitant dosing with NTG somewhat attenuated this effect.
Intermittent treatment with the short-acting NTG decreased the size of an experimentally induced myocardial infarct by promoting coronary collateral development. These new insights are of great relevance for future clinical strategies for the treatment of occlusive vascular diseases.
在冠状动脉阻塞的情况下，预先存在的小侧支血管（小动脉）会发育成更大的动脉（生理性旁路），这些旁路有可能允许阻塞远端的一定程度的灌注。这种现象称为血管生成，它通过一系列复杂的事件发生，一氧化氮（NO）起着至关重要的作用。本研究的目的是研究补充给予一氧化氮供体（即短效硝酸甘油（NTG）或缓释硝酸异山梨酯（ISDN））对大鼠重复性冠状动脉闭塞模型中侧支血管发育的影响。
通过对大鼠左前降支冠状动脉（LAD）的重复闭塞方案（ROP）诱导冠状动脉侧支生长。主要终点是大鼠心脏梗死面积的组织学评估和 LAD 最终永久性闭塞时 ST 段抬高（心电图分析）（实验性诱导的心肌梗死）。还通过 ROP 期间 5 天的给药评估了 NTG 或 ISDN 的作用。我们还研究了同时给予 NTG 是否可以补偿乙酰水杨酸（ASA）的抗血管生成作用。
在 ROP 5 天后，平均梗死面积和 ST 段抬高程度仅略低于 SHAM 组；然而，在方案 10 天后，ROP 组显示出明显较轻的梗死损伤，表明增强了血管生成。间歇性 NTG 给药大大降低了 ST 段抬高和梗死面积。ISDN 也对血管生成有积极作用，但不如 NTG 明显。ASA 的给药增加了梗死的严重程度；然而，同时给予 NTG 可在一定程度上减弱这种作用。
短效 NTG 的间歇性治疗通过促进冠状动脉侧支血管发育，减少了实验性诱导的心肌梗死的大小。这些新的见解对于阻塞性血管疾病治疗的未来临床策略具有重要意义。
