Polymyxin B, a protein kinase C inhibitor, abolishes preconditioning-induced protection against contractile dysfunction in the isolated blood perfused rat heart.
Polymyxin B, a protein kinase C inhibitor, abolishes preconditioning-induced protection against contractile dysfunction in the isolated blood perfused rat heart.
复制标题
多粘菌素 B 是一种蛋白激酶 C 抑制剂，可消除预处理诱导的针对离体血液灌注大鼠心脏收缩功能障碍的保护作用。
DOI：
10.1006/jmcc.1996.0091
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Apstein,CS
中科院分区：
文献类型：
--
作者：
Cave,AC;Apstein,CS
本研究的目的是：（1）确定在存在生理性底物组合的情况下，在血液灌流的离体心脏模型中预处理对抗收缩功能障碍的特征;（2）确定蛋白激酶C（PKC）是否参与该模型中的预处理。为了研究这些目的，分离等容，血液灌流大鼠心脏（左心室球囊，n=6/组）正常氧灌注30分钟，然后分为三组，并进行：（1）再灌注30分钟（2）再灌注20 min+缺血5 min再灌注5 min（3）3×（缺血5 min+再灌注5 min）（3×预处理组）。然后所有心脏进行30分钟的缺血和30分钟的再灌注。测定收缩功能、心肌耗氧量（MVO 2）、乳酸释放和肌酸激酶释放。为了确定PKC是否参与该模型中的预处理机制，在存在相对特异性PKC抑制剂多粘菌素B（50μm）的情况下重复对照组和3×预处理组实验。对照组、1×和3×预处理组的LVDP最终恢复率分别为31±12、67±6和60±5%。收缩功能的保护伴随着舒张功能和MVO 2与收缩功能的比率（代谢：机械效率的比率）的保护。然而，乳酸释放仅在3×预处理组中减少。多粘菌素B可阻断预处理对心肌收缩和舒张功能的保护作用，并阻断对MVO 2与心肌收缩功能比值的保护作用。然而，在多粘菌素B预处理组中乳酸盐释放仍然减少。因此，预处理诱导的保护收缩功能障碍似乎伴随着保存舒张功能和代谢：机械效率，是有效的存在下的生理组合的基板。然而，通过乳酸释放评估的缺血期间糖酵解的限制似乎是预处理方案的附带现象，并不总是与保护相关。PKC激活似乎是对收缩功能障碍的保护机制的关键，因为多粘菌素B的管理取消了任何保护。
The aims of this study were (1) to determine the characteristics of preconditioning against contractile dysfunction in a blood perfused isolated heart model in the presence of a physiologic combination of substrates, and (2) to determine if protein kinase C (PKC) is involved in preconditioning in this model. In order to investigate these aims, isolated isovolumic, blood perfused rat hearts (balloon-in-LV,n=6/group) were perfused normoxically for 30 min and then divided into three groups and subjected to: (1) a further 30 min of perfusion (control group) (2) a further 20 min of perfusion+5 min of ischaemia and 5 min of reperfusion (1×preconditioned group) and (3) 3×(5 min of ischaemia+5 min of reperfusion) (3×preconditioned group). All hearts were then subjected to 30 min of ischaemia and 30 min of reperfusion. Contractile function, myocardial oxygen consumption (MVO2), lactate release and creatine kinase release were all assessed. To determine if PKC is involved in the mechanism of preconditioning in this model, the control and 3×preconditioned group experiments were repeated in the presence of polymyxin B (50μm), a relatively specific PKC inhibitor. Final recovery of LVDP was 31±12, 67±6 and 60±5% in the control, 1× and 3×preconditioned groups, respectively. Protection of contractile function was accompanied by both a preservation of diastolic function and the ratio of MVO2to contractile function (ratio of metabolic:mechanical efficiency). However, lactate release was decreased only in the 3×preconditioned group. Polymyxin B abolished preconditioning-induced protection against contractile and diastolic dysfunction and the protection of the ratio of MVO2to contractile function. Lactate release was still however reduced in the polymyxin B-preconditioned group. Thus, preconditioning-induced protection against contractile dysfunction appears to be accompanied by a preservation of both diastolic function and the metabolic:mechanical efficiency and is effective in the presence of a physiologic combination of substrates. However, limitation of glycolysis during ischaemia, as assessed by lactate release, appears to be an epiphenomenon of the preconditioning protocol and is not consistently related to protection. PKC activation appears to be pivotal to the mechanism of protection against contractile dysfunction, since administration of polymyxin B abolished any protection.