MODULATION OF MYOFILAMENT CA2+ SENSITIVITY AS A POSITIVE INOTROPIC INTERVENTION

调节肌丝 CA2 敏感性作为积极的正性肌力干预

• 批准号: 3802245
• 负责人: G GAMBASSI
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3802245
• 关键词: calcium transporting ATPase; cardiotonic agents; fluorescent dye /probe; guinea pigs; heart cell; heart contraction; heart failure; heart pharmacology; muscle proteins; myocardium; myofibrils; pharmacokinetics; phosphodiesterase inhibitors; thiadiazine

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.

心肌收缩力的增加最终是由于 两种机制之一：增强的细胞内游离Ca 2+浓度 （CAI）或收缩蛋白的Ca 2+敏感性增加。 几乎所有传统干预措施都会改变幅度和/或 CAI瞬态的时间过程。 这些心脏毒剂的价值是 受到不希望的效果的严格限制。 在新的积极肌肉中 物质硫二嗪衍生物，EMD 53998（由E. Merck设计， 德国达姆施塔特（Darmstadt）采取了混合行动。 在皮肤的心肌纤维中 对增加峰值力并向左移动PCA-具有有效的效果 力关系，在细胞匀浆中表现出磷酸二酯酶 （PDE）抑制活性。 但是，肌丝的效力 相对于PDE抑制的致敏性大于任何 迄今为止可用的物质。 我们测试了EMD 53998及其效果 对映异构体（EMD 57033和EMD 57439）在完整的豚鼠心脏细胞中， 在室温下以Hepes缓冲液沐浴，并充满荧光 Ca 2+指标，Indo-1。 我们的目的是确定是否光学 对映异构体，（+），EMD 57033和（ - ），EMD 57439可以 立体选择性将通过PDE抑制介导的效果与 通过增加对Ca 2+的肌丝反应性获得的。 这 结果表明，这三种物质施加明显增加 抽搐幅度伴随着缩短速度的平行变化。 CAI瞬态增加了EMD 53998和EMD 57439； （+） - 相反，对映异构体并未改变收缩期或 [收缩期舒张] Ca 2+级别。 这些结果表明小说 （+）对映异构体的表现为完整的纯肌丝Ca 2+敏化器 细胞并可能具有某些形式的心力衰竭的治疗潜力。