Positive inotropy mediated by diacylglycerol in rat ventricular myocytes.
Positive inotropy mediated by diacylglycerol in rat ventricular myocytes.
复制标题
大鼠心室肌细胞中二酰甘油介导的正性肌力。
DOI：
10.1161/01.res.81.1.92
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发表时间：
1997
影响因子：
20.1
通讯作者：
Walker,JW
中科院分区：
文献类型：
--
作者：
Pi,Y;Sreekumar,R;Huang,X;Walker,JW
许多神经激素刺激哺乳动物心脏中的磷脂水解并升高甘油二酯，但这些细胞内事件的生理后果尚不清楚。在本研究中，通过使用光敏笼状化合物在成年大鼠心室肌细胞内释放二酰基甘油类似物二辛酰甘油（diC 8），研究了二酰基甘油对心肌收缩的调节。这种方法使我们能够避免心肌细胞暴露于细胞外的diC 8，还可以控制释放到细胞中的diC 8的量。diC 8的光释放使电起搏肌细胞（0.5 Hz，1 mmol/L Ca 2+林格氏溶液[pH 7.4]，22°C）的抽搐幅度缓慢发展（半衰期，1.9±0.1分钟; n=26）但稳健（406±42%）增强。这种正性肌力作用是剂量依赖性的，对diC 8的S-对映体具有立体特异性，通过花生四烯酸协同增强，并通过蛋白激酶C抑制剂白屈菜红碱阻断。这些数据提供的证据表明，甘油二酯可以诱导哺乳动物心室肌强的正性肌力作用，可能是通过激活蛋白激酶C。相比之下，根据先前的报道，将diC 8细胞外灌注到肌细胞上导致抽搐幅度下降42±2%。为了解释这种对diC 8如何应用的依赖性，我们假设diC 8在细胞内和细胞外位点具有不同的生理作用。肽神经激素内皮素-1，提高二酰基甘油在心脏组织中，产生了积极的正性肌力作用，这是类似的光释放diC 8的反应。二酰基甘油/蛋白激酶C途径现在已经成为一个很好的候选调解人的至少一个组件的正性肌力相关的代理，刺激磷脂周转在成年哺乳动物心肌。
Many neurohormones stimulate phospholipid hydrolysis and elevate diacylglycerol in the mammalian heart, but the physiological consequences of these intracellular events are unclear. Regulation of myocardial contraction by diacylglycerol was investigated in the present study by releasing the diacylglycerol analogue dioctanoylglycerol (diC8) within adult rat ventricular myocytes by using a light-sensitive caged compound. This approach permitted us to avoid exposure of myocytes to extracellular diC8and yet to control the amount of diC8released into the cells. Photorelease of diC8produced a slowly developing (half-time, 1.9±0.1 minute; n=26) but robust (406±42%) enhancement of twitch amplitude in electrically paced myocytes (0.5 Hz, 1 mmol/L Ca2+Ringer’s solution [pH 7.4], 22°C). This positive inotropic effect was dose dependent, stereospecific for the S-enantiomer of diC8, synergistically enhanced by arachidonic acid, and blocked by the protein kinase C inhibitor chelerythrine. The data provide evidence that diacylglycerol can induce a strong positive inotropic effect in mammalian ventricular muscle, possibly by activating protein kinase C. By contrast, perfusion of diC8extracellularly onto myocytes caused a 42±2% decline in twitch amplitude, in accordance with previous reports. To account for this dependence on how diC8is applied, we postulate that diC8has distinct physiological actions at intracellular and extracellular sites. The peptide neurohormone endothelin-1, which elevates diacylglycerol in cardiac tissues, produced a positive inotropic effect that was similar to the response to photoreleased diC8. The diacylglycerol/protein kinase C pathway has now become a good candidate for mediator of at least a component of the positive inotropy associated with agents that stimulate phospholipid turnover in adult mammalian myocardium.