IMPORTANCE OF METABOLIC INHIBITION AND CELLULAR PH IN MEDIATING PRECONDITIONING CONTRACTILE AND METABOLIC EFFECTS IN RAT HEARTS
IMPORTANCE OF METABOLIC INHIBITION AND CELLULAR PH IN MEDIATING PRECONDITIONING CONTRACTILE AND METABOLIC EFFECTS IN RAT HEARTS
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DOI：
10.1161/01.res.74.1.139
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发表时间：
1994-01-01
影响因子：
20.1
通讯作者：
WEISS, RG
中科院分区：
文献类型：
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作者：
DEALBUQUERQUE, CP;GERSTENBLITH, G;WEISS, RG
缺血预处理（IPC）是在长时间缺血前短暂中断血流，增加心肌缺血耐受性，改善再灌注心肌功能的病理生理机制，目前尚不完全清楚。为了测试是否短期的代谢抑制在流量减少的情况下诱导类似的保护作用，我们研究了心脏功能和代谢，使用P-31核磁共振波谱在离体等容大鼠心脏。15只心脏接受IPC，包括2个5 min缺血再灌注循环（IPC组）; 18只心脏接受短暂代谢抑制，包括2次5 min 10 mmol/L氰化钠灌注（CN组）; 15只心脏作为对照。随后，所有心脏在37 ℃下进行30分钟的全脑缺血，然后再灌注。在缺血期结束时，磷酸肌酸和ATP水平在各组之间没有差异。然而，CN组（6.51 +/- 0.03）和IPC组（6.12 +/- 0.06）的细胞pH稳定在比对照组（5.84 +/- 0.01，P <0.001）更高的水平。IPC和CN心脏的功能和代谢恢复优于对照心脏。改善的收缩恢复与再灌注时的冠状动脉流速（r = 0.7，P <0.001）和缺血30分钟时的pH值（r = 0.8，P <0.001）相关，但与缺血期间ATP水平的增加无关。以15 mL/min的流速对其他对照心脏进行再灌注，以匹配IPC和CN组的流速，但这并未导致性能改善。为了检验这一假设，即预处理的效果是相关的PI-II在缺血期间，额外的IPC和CN心脏进行了相同的预处理方案，除了细胞的pH值降低在缺血期结束时，通过使用高碳酸盐超融合在缺血期间或通过使用无重碳酸盐灌注液之前持续缺血。这两种干预措施导致收缩和代谢恢复显著低于其他IPC和CN心脏中观察到的结果。因此，预处理效应不需要减少冠状动脉流量，但可以有效地引起代谢抑制本身在这个模型中。保护作用不依赖于保存全局心肌能量储存，而是依赖于在延长的缺血期减少酸中毒。
The pathophysiological mechanisms by which brief periods of flow interruption before a prolonged ischemic period, ischemic preconditioning (IPC), increase myocardial tolerance to ischemia and improve myocardial function during reperfusion are not completely understood. To test whether short periods of metabolic inhibition in the absence of a flow reduction induce similar protective effects, we studied cardiac function and metabolism using P-31 nuclear magnetic resonance spectroscopy in isolated isovolumic rat hearts. Fifteen hearts underwent IPC, consisting of two 5-minute ischemia-reperfusion cycles (IPC group); 18 hearts underwent brief metabolic inhibition by exposure to two 5-minute infusions of 10 mmol/L sodium cyanide (CN group); and 15 hearts served as controls. Subsequently, all hearts were subjected to 30 minutes of total global ischemia at 37 degrees C followed by reperfusion. At the end of the ischemic period, creatine phosphate and ATP levels did not differ among the groups. Cellular pH, however, plateaued at a higher level in the CN group (6.51 +/- 0.03) and IPC group (6.12 +/- 0.06) than in the control group (5.84 +/- 0.01, P < .001). IPC and CN hearts had better functional and metabolic recovery than the control hearts. Improved contractile recovery correlated with coronary flow rates at reperfusion (r = .7, P < .001) and with pH, values at 30 minutes of ischemia (r = .8, P < .001) but not with increased ATP levels during ischemia. Additional control hearts were reperfused at 15 mL/min so as to match the flow rates of IPC and CN groups, but this did not result in improved performance. To test the hypothesis that the preconditioning effect was related to pi-Ii during ischemia, additional IPC and CN hearts underwent the same preconditioning protocol, except that the cellular pH at the end of the ischemic period was lowered by the use of hypercarbic super fusion during ischemia or by the use of bicarbonate-free perfusate just before sustained ischemia. Both of these interventions resulted in significantly lower contractile and metabolic recoveries than those observed in other IPC and CN hearts. Therefore, the preconditioning effect does not require reduced coronary flow but can be effectively elicited by metabolic inhibition per se in this model. The protective effect is not dependent on preservation of global myocardial energy stores but, rather, on reduced acidosis during the prolonged ischemic period.