King L M, Boucher F, Opie L H
Rayne Institute, St Thomas' Hospital, London, UK.
J Mol Cell Cardiol. 1995 Jan;27(1):701-20. doi: 10.1016/s0022-2828(08)80061-2.
Ischemic contracture may be avoided by the provision of glucose under low flow conditions (Owen et al., 1990). However, accumulation of harmful metabolic end products may inhibit glycolytic flux and lessen the benefit of glucose. We assessed whether during increasingly severe flow restriction, provision of glucose might be harmful rather than beneficial, using the Langendorff perfused rat heart. Ischemic contracture (resting tension expressed as percent of preischemic developed pressure) was measured via a left ventricular balloon. Reductions in flow to 0, 0.015, 0.03, 0.06, 0.1, 0.2 or 0.4 ml/min/g wet wt over 60 min were tested. At zero flow, peak contracture was 61.4 +/- 3.5% (+/- S.E.) but fell to 15.6 +/- 6.3% with 0.4 ml/min/g wet wt (P < 0.05) in the presence of 11 mmol/l glucose. Time-to-onset of contracture was significantly delayed by the higher coronary flows. At coronary flows down to zero, the effect of glucose was inconstant or absent, but not harmful. With the residual flow at 0.2 ml/min/g wet wt, a dose response to glucose in ischemia was elicited, using concentrations of 0, 2.5, 5.5, 11 or 22 mmol/l. Maximum protection against ischemic contracture was found with 11 mmol/l glucose. However, once contracture occurred, functional recovery was severely impaired in all cases. Reducing glycogen prior to low flow ischemia (0.2 ml/min/g wet wt) with 11 mmol/l glucose increased peak contracture, and reduced the time-to-onset of contracture. Increased preischemic glycogen had little effect on contracture. Glycolytic flux fell in proportion to the coronary flow. However, there was an increased glucose extraction at lower flows of 0.1 and 0.2 ml/min/g wet wt, suggesting that it is the rate of delivery (i.e. coronary flow) which is the rate limiting step rather than enzyme inhibition by accumulated metabolites. If flow were further reduced, metabolite accumulation would become more important, such that with no flow, this would be the determinant of glycolytic flux rate. In our model, the two requirements for optimal protection from ischemia were (i) provision of glucose (11 mmol/l was optimal) and (ii) an adequate coronary flow to deliver the glucose and remove end product inhibition (greater than 0.06 ml/min/g wet wt).
在低流量条件下提供葡萄糖可避免缺血性挛缩（欧文等人，1990年）。然而，有害代谢终产物的积累可能会抑制糖酵解通量并降低葡萄糖的益处。我们使用Langendorff灌注大鼠心脏评估在血流限制日益严重的情况下，提供葡萄糖是否可能有害而非有益。通过左心室球囊测量缺血性挛缩（静息张力表示为缺血前发展压力的百分比）。测试了在60分钟内将流量降至0、0.015、0.03、0.06、0.1、0.2或0.4 ml/min/g湿重的情况。在零流量时，峰值挛缩为61.4±3.5%（±标准误），但在存在11 mmol/l葡萄糖的情况下，当流量为0.4 ml/min/g湿重时降至15.6±6.3%（P<0.05）。较高的冠状动脉流量显著延迟了挛缩的发作时间。在冠状动脉流量降至零时，葡萄糖的作用不稳定或不存在，但无害。在残余流量为0.2 ml/min/g湿重的情况下，使用0、2.5、5.5、11或22 mmol/l的浓度引发了缺血时对葡萄糖的剂量反应。发现11 mmol/l葡萄糖对缺血性挛缩具有最大保护作用。然而，一旦发生挛缩，所有情况下的功能恢复都严重受损。在低流量缺血（0.2 ml/min/g湿重）前用11 mmol/l葡萄糖降低糖原会增加峰值挛缩，并缩短挛缩发作时间。缺血前糖原增加对挛缩影响不大。糖酵解通量与冠状动脉流量成比例下降。然而，在较低流量0.1和0.2 ml/min/g湿重时葡萄糖摄取增加，这表明限制步骤是输送速率（即冠状动脉流量）而非积累代谢物对酶的抑制。如果流量进一步降低，代谢物积累将变得更加重要，以至于在无流量时，这将是糖酵解通量速率的决定因素。在我们的模型中，最佳保护免受缺血的两个要求是：（i）提供葡萄糖（11 mmol/l最佳）和（ii）足够的冠状动脉流量以输送葡萄糖并消除终产物抑制（大于0.06 ml/min/g湿重）。
