Shinmura K, Tang X L, Takano H, Hill M, Bolli R
Experimental Research Laboratory, Division of Cardiology, University of Louisville and Jewish Hospital Heart and Lung Institute, Louisville, Kentucky 40292, USA.
Am J Physiol. 1999 Dec;277(6):H2495-503. doi: 10.1152/ajpheart.1999.277.6.H2495.
Although previous studies suggested that the protection of late preconditioning (PC) against myocardial stunning is mediated by nitric oxide (NO), direct evidence that exogenous administration of NO attenuates myocardial stunning is lacking. Furthermore, although exogenous NO administration was shown to elicit a late PC phase, it is unknown whether NO donors also induce an early PC phase. Therefore, conscious rabbits underwent two experimental stages (3 days of six 4-min occlusion/4-min reperfusion cycles each) 2 wk apart. In study I, both stages were control stages (n = 7). In studies II and III, stage I was the control stage. On day 1 of stage II, seven rabbits received infusion of nitroglycerin (NTG; 2 microg. kg(-1). min(-1) iv) during the ischemia-reperfusion sequence, starting 30 min before the 1st occlusion and ending 10 min after the 6th reperfusion (study II). Another seven rabbits received infusion of NTG (2 microg. kg(-1). min(-1) iv) for 1 h followed by a 30-min washout interval and then underwent six 4-min occlusion/4-min reperfusion cycles (study III). In the control stage of all three studies, recovery of wall thickening (WTh) after occlusion/reperfusion cycles was markedly enhanced on days 2 and 3 compared with day 1, indicating late PC. In study II, infusion of NTG during the occlusion/reperfusion cycles on day 1 resulted in significant and sustained enhancement in WTh recovery. A similar attenuation of stunning was observed in study IV in six rabbits given intravenous infusion of S-nitroso-N-acetylpenicillamine (SNAP) during occlusion/reperfusion cycles. The magnitude of the protection afforded by NTG and SNAP was comparable to that afforded by the late ischemic PC phase. In contrast, in study III infusion of NTG before occlusion/reperfusion cycles did not enhance WTh recovery, indicating that NTG failed to induce an early PC effect against stunning. This study demonstrates that administration of hemodynamically inactive doses of two unrelated NO donors alleviates myocardial stunning in conscious rabbits, providing direct evidence for a protective action of NO in this setting.
尽管先前的研究表明，晚期预处理（PC）对心肌顿抑的保护作用是由一氧化氮（NO）介导的，但缺乏外源性给予NO可减轻心肌顿抑的直接证据。此外，尽管已表明外源性给予NO可引发晚期PC阶段，但尚不清楚NO供体是否也能诱导早期PC阶段。因此，清醒兔在相隔2周的时间内经历两个实验阶段（每个阶段进行6个4分钟阻断/4分钟再灌注循环，共3天）。在研究I中，两个阶段均为对照阶段（n = 7）。在研究II和III中，阶段I为对照阶段。在阶段II的第1天，7只兔在缺血-再灌注过程中接受硝酸甘油（NTG；2μg·kg⁻¹·min⁻¹静脉注射）输注，从第1次阻断前30分钟开始，至第6次再灌注后10分钟结束（研究II）。另外7只兔接受NTG（2μg·kg⁻¹·min⁻¹静脉注射）输注1小时，随后有30分钟的洗脱期，然后进行6个4分钟阻断/4分钟再灌注循环（研究III）。在所有三项研究的对照阶段，与第1天相比，阻断/再灌注循环后第2天和第3天室壁增厚（WTh）的恢复明显增强，表明存在晚期PC。在研究II中，第1天在阻断/再灌注循环期间输注NTG导致WTh恢复显著且持续增强。在研究IV中，6只兔在阻断/再灌注循环期间静脉输注S-亚硝基-N-乙酰青霉胺（SNAP）时，也观察到了类似的顿抑减轻。NTG和SNAP提供的保护程度与晚期缺血性PC阶段提供的保护程度相当。相比之下，在研究III中，在阻断/再灌注循环前输注NTG并未增强WTh恢复，表明NTG未能诱导针对顿抑的早期PC效应。本研究表明，给予两种不相关的NO供体的血流动力学无活性剂量可减轻清醒兔的心肌顿抑，为NO在此情况下的保护作用提供了直接证据。
