Vanoverschelde J L, Janier M F, Bergmann S R
Cardiovascular Division, Washington University School of Medicine, St Louis, MO 63110.
Circ Res. 1994 May;74(5):817-28. doi: 10.1161/01.res.74.5.817.
The mechanical effects of ischemic contracture may be important in the development of irreversible cellular damage as it increases mechanical stress on sarcolemmal membranes and restricts endocardial perfusion. To assess the relative importance of these mechanical effects compared with decreased energy supply in the development of irreversible injury, the effects of inhibiting ischemic contracture with 2,3-butanedione monoxime (BDM), an agent that disrupts excitation-contraction coupling, were delineated in isovolumically contracting isolated rabbit hearts. Administration of 20 mmol/L BDM in 12 hearts subjected to 60 minutes of low-flow ischemia prevented ischemic contracture (left ventricular end-diastolic pressure [LVEDP], 12 +/- 3 compared with 48 +/- 14 mm Hg in 20 control hearts; P < .001), reduced membrane damage (creatine kinase [CK] release, -54% compared with control hearts; P < .05), and enhanced functional recovery during reperfusion (left ventricular developed pressure [LVDP], 86 +/- 10% of baseline compared with 56 +/- 23% in control hearts; P < .01). These observations were not related to increased intracavitary pressure and its effects on flow distribution, since venting the left ventricle in additional hearts did not result in improved function during reperfusion. Although it would be tempting to conclude that BDM protected ischemic myocardium by preventing ischemic contracture, administration of BDM was also associated with reduced depletion of ATP during ischemia, perhaps related to diminished energy demand. To distinguish between the relative importance of inhibiting contracture from provision of adequate energy, the period of ischemia was extended to 120 minutes. BDM still prevented ischemic contracture (LVEDP, 10 +/- 6 mm Hg) and preserved ATP stores, but it did not prevent membrane damage (CK release, 483 +/- 254 U/g dry weight) or contractile failure during reperfusion (LVDP, 68 +/- 7% of baseline). In contrast, increasing the rate of anaerobic glycolysis during ischemia by doubling glucose and insulin in the presence of BDM markedly decreased membrane damage (CK release, 114 +/- 72 U/g dry weight; P < .05) and contractile failure during reperfusion (LVDP, 88 +/- 7% recovery of baseline; P < .01). These results suggest that insufficient energy production is primarily responsible for myocardial ischemic damage, whereas mechanical effects of ischemic contracture appear to play only a minor role.
缺血性挛缩的机械效应在不可逆细胞损伤的发生过程中可能很重要，因为它会增加肌膜上的机械应力并限制心内膜灌注。为了评估这些机械效应与能量供应减少相比在不可逆损伤发生过程中的相对重要性，在等容收缩的离体兔心脏中，研究了用2,3-丁二酮一肟（BDM，一种破坏兴奋-收缩偶联的药物）抑制缺血性挛缩的效果。在12颗经历60分钟低流量缺血的心脏中给予20 mmol/L BDM可预防缺血性挛缩（左心室舒张末期压力[LVEDP]，12±3 mmHg，而20颗对照心脏为48±14 mmHg；P<.001），减少膜损伤（肌酸激酶[CK]释放，与对照心脏相比减少-54%；P<.05），并增强再灌注期间的功能恢复（左心室发育压力[LVDP]，为基线的86±10%，而对照心脏为56±23%；P<.01）。这些观察结果与腔内压力增加及其对血流分布的影响无关，因为在另外一些心脏中对左心室进行排气并没有导致再灌注期间功能改善。尽管很容易得出BDM通过预防缺血性挛缩来保护缺血心肌的结论，但给予BDM也与缺血期间ATP消耗减少有关，这可能与能量需求减少有关。为了区分抑制挛缩与提供充足能量的相对重要性，将缺血时间延长至120分钟。BDM仍然可以预防缺血性挛缩（LVEDP，10±6 mmHg）并保留ATP储备，但它不能预防膜损伤（CK释放，483±254 U/g干重）或再灌注期间的收缩功能衰竭（LVDP，为基线的68±7%）。相比之下，在BDM存在的情况下将葡萄糖和胰岛素加倍以增加缺血期间无氧糖酵解的速率，可显著减少膜损伤（CK释放，114±72 U/g干重；P<.05）和再灌注期间的收缩功能衰竭（LVDP，恢复至基线的88±7%；P<.01）。这些结果表明，能量产生不足是心肌缺血损伤的主要原因，而缺血性挛缩的机械效应似乎只起次要作用。
