MODULATION OF MYOFILAMENT CA2+ SENSITIVITY AS A POSITIVE INOTROPIC INTERVENTION

心肌收缩力量的增加最终归因于 两种机制之一：提高细胞内游离钙浓度 (CaI)或增加收缩蛋白的钙敏感性。 几乎所有的传统干预措施都会改变波幅和/或 蔡氏瞬变的时间进程。这些强心剂的价值是 受到不良影响的严重限制。在新的正性肌力药中 物质噻二氮酮衍生物，EMD 53998(由E.Merck设计， 德国达姆施塔特)的行动喜忧参半。在有皮肤的心肌纤维中 有一个强大的作用，增加峰值力量和左移的PCA- 力关系，并在细胞匀浆中显示磷酸二酯酶 (PDE)抑制活性。然而，肌丝的效力 相对于PDE抑制的敏化作用比任何 到目前为止可用的物质。我们测试了EMD 53998及其 对映体(EMD 57033和EMD 57439)在完整的豚鼠心肌细胞中， 在室温下，在赫普斯缓冲液中沐浴，并装载荧光 钙指示剂，INDO-1。我们的目标是确定光学系统 对映体，(+)，EMD 57033和(-)，EMD 57439可以 立体选择性地分离通过PDE抑制介导的作用 这是通过增加肌丝对钙的反应性而获得的。这个 结果表明，这三种物质都显著增加了 抽动幅度伴随着缩短速度的平行变化。 蔡氏瞬变增加53998和57439；(+)- 相反，对映体既不改变收缩压，也不改变 [收缩-舒张期]钙水平。这些结果表明，这部小说 (+)对映体在完整状态下表现为纯肌丝钙增敏剂 细胞，并可能对某些形式的心力衰竭有治疗潜力。

The increase in the force of myocardial contraction is ultimately due to one of two mechanisms: an enhanced intracellular free Ca 2+ concentration (Cai) or an increased Ca 2+ sensitivity of the contractile proteins. Virtually all the traditional interventions do alter the amplitude and/or the time course of Cai transient. The value of these cardiotonic agents is severely limited by undesired effects. Among the new positive inotropic substances the thiadiazinone derivative, EMD 53998 (designed by E. Merck, Darmstadt, Germany) has a mixed action. In skinned myocardial fibers it has a potent effect to increase peak force and to shift leftward the pCa- force relationship, and in cell homogenates exhibits phosphodiesterase (PDE) inhibitory activity. However, the potency of myofilament sensitization relative to that of PDE inhibition is greater than for any substance available to date. We tested the effect of EMD 53998 and of its enantiomers (EMD 57033 and EMD 57439) in intact guinea pig cardiac cells, bathed in Hepes buffer, at room temperature and loaded with the fluorescent Ca 2+ indicator, Indo-1. Our aim was to ascertain whether optical enantiomers, the (+), EMD 57033 and the (-), EMD 57439 could stereoselectively separate the effect mediated through PDE inhibition from that obtained via an increased myofilament responsiveness to Ca 2+. The results show that all three substances exert a pronounced increase in twitch amplitude accompanied by parallel changes in velocity of shortening. The Cai transient was increased by EMD 53998 and EMD 57439; the (+)- enantiomer, on the contrary, did not change either the systolic or the [systolic-diastolic] Ca 2+ levels. These results indicate that the novel (+) enantiomer behaves as a pure myofilament Ca 2+ sensitizer in intact cells and may have therapeutic potential in some forms of heart failure.