Sargent C A, Wilde M W, Dzwonczyk S, Tuttle J G, Murray H N, Atwal K, Grover G J
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Cardiovasc Res. 1996 Feb;31(2):270-7.
A myocardial calcium-independent PLA2 has been described that is activated during myocardial ischemia and this enzyme may modulate ATP-sensitive potassium channels (KATP). The aim of this study was to determine the effect of an inhibitor of this enzyme, a bromoenol lactone, in isolated globally ischemic rat hearts.
Isolated rat hearts were treated for 10 min with 0.3-6 microM bromoenol lactone and then subjected to 25 min ischemia and 30 min reperfusion.
The bromoenol lactone significantly increased coronary flow in nonischemic myocardium, and slightly reduced cardiac function at 6 microM. During global ischemia, time to contracture was significantly increased from vehicle group values in the presence of the bromoenol lactone (EC50 = 1.2 microM). During reperfusion, a concentration-dependent increase in function and a reduction in LDH release were observed for the PLA2 inhibitor. The concentrations of the PLA2 inhibitor which were significantly cardioprotective, inhibited this enzyme in membrane fractions of rat myocardium (IC50 = 0.87 microM). The KATP blocker sodium 5-hydroxydecanoate (5-HD) inhibited the increase in time to contracture observed for the bromoenol lactone. During reperfusion, 5-HD abolished the protective effects of the bromoenol lactone on cardiac function and LDH release. Glyburide had similar effects on the cardioprotective activity of the bromoenol lactone, although it only partially abolished the LDH reducing effect of this agent.
The bromoenol lactone protects ischemic myocardium at concentrations which also inhibit calcium-independent PLA2. This cardioprotection can be attenuated by blockers of KATP, suggesting a potential mechanism for modulation of myocardial KATP.
已描述了一种心肌钙非依赖性磷脂酶A2，其在心肌缺血期间被激活，且该酶可能调节ATP敏感性钾通道（KATP）。本研究的目的是确定该酶的抑制剂溴代烯醇内酯对离体全心缺血大鼠心脏的影响。
将离体大鼠心脏用0.3 - 6微摩尔的溴代烯醇内酯处理10分钟，然后进行25分钟的缺血和30分钟的再灌注。
溴代烯醇内酯显著增加非缺血心肌的冠脉血流，在6微摩尔时轻微降低心脏功能。在全心缺血期间，在存在溴代烯醇内酯的情况下，出现挛缩的时间较溶剂组显著延长（半数有效浓度=1.2微摩尔）。在再灌注期间，可以观察到磷脂酶A2抑制剂使心脏功能呈浓度依赖性增加，乳酸脱氢酶释放减少。具有显著心脏保护作用的磷脂酶A2抑制剂浓度，可抑制大鼠心肌膜组分中的该酶（半数抑制浓度=0.87微摩尔）。KATP阻断剂5 - 羟基癸酸钠（5 - HD）抑制了溴代烯醇内酯所观察到的挛缩时间增加。在再灌注期间，5 - HD消除了溴代烯醇内酯对心脏功能和乳酸脱氢酶释放的保护作用。格列本脲对溴代烯醇内酯的心脏保护活性有类似作用，尽管它仅部分消除了该药物降低乳酸脱氢酶的作用。
溴代烯醇内酯在抑制钙非依赖性磷脂酶A2的浓度下可保护缺血心肌。这种心脏保护作用可被KATP阻断剂减弱，提示了一种调节心肌KATP的潜在机制。
