DECREASED CALCIUM SENSITIVITY IN STUNNED CARDIAC MYOCYTE

震惊的心肌细胞钙敏感性降低

基本信息

  • 批准号:
    3368506
  • 负责人:
  • 金额:
    $ 18.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1993
  • 资助国家:
    美国
  • 起止时间:
    1993-01-01 至 1995-12-31
  • 项目状态:
    已结题

项目摘要

The reversible mechanical dysfunction that persists during reperfusion following brief periods of myocardial ischemia has been termed postischemic myocardial stunning. The objective of this proposal is to investigate possible mechanisms of this clinically important phenomenon. The main hypothesis to be tested is that decreased myofilament Ca2+ sensitivity is an important cause of depressed function in postischemic stunned myocardium. The approach that will be employed combines an in vivo reperfusion model of stunned myocardium with physiological and biochemical measurements on an in vitro preparation of permeabilized myocardium. Stunning will be induced in the LAD bed of an open-chest pig heart preparation in which regional myocardial function will be assessed from the load independent relationship between end-systolic pressure and wall thickness. Single cell-sized preparations of skinned myocardium will be obtained by mechanical disruption of small needle biopsies from the LAD perfusion bed of pig myocardium. Tension-pCa relationships assessed in these preparations will provide a direct measure of myofilament Ca2+ sensitivity. Preliminary data from our laboratory using this approach show a significant decrease in myofilament Ca2+ sensitivity in stunned myocardium. This proposal has four specific aims: (1) To further characterize the relationship between in vivo measures of postischemic mechanical dysfunction and in vitro measure of myofilament Ca2+ sensitivity from the same heart. A positive relation would suggest that reduced sensitivity to Ca2+ is a direct mechanism of ventricular dysfunction. (2) To determine whether decreases in myofilament Ca2+ sensitivity occur during ischemia, reperfusion, or both. Serial measures of myofilament Ca2+ sensitivity from control, ischemic, and postischemic stunned myocardium obtained from the same hearts should indicate whether reperfusion injury occurs and is an independent cause of stunning. The role of extracellular calcium in reperfusion injury will be tested both in vivo and in vitro. (3) To determine whether decreased myofilament Ca2+ sensitivity is secondary to abnormalities in the regulatory protein troponin and its subunits, troponin-C,-I, and-T. Tension-pCa relationships from stunned myocardium will be compared after extraction of endogenous troponin and replacement with control troponin. (4) To assess a possible role of phosphorylation of troponin I as a mechanism of postischemic stunning. Because phosphorylation of troponin I is a well characterized cause of decreased myofilament Ca2+ sensitivity in normal myocardium, the effect of treatment with phosphatase on tension- pCa relationships from control and stunned myocardium will be measured and compared. Studies proposed in this application will allow direct assessment of decreased sensitivity of myofilaments to Ca2+ as a mechanism of myocardial stunning, and will provide tests of possible mechanisms of stunning at the levels of the myofilaments and regulatory proteins.
再灌注期间持续存在的可逆性机械功能障碍 在短暂的心肌缺血之后, 缺血后心肌顿抑 这项建议的目的是 研究这种临床重要现象的可能机制。 待检验的主要假设是肌丝Ca 2+减少 敏感性是缺血后功能低下的重要原因 心肌顿抑 将采用的方法结合了一种 在体顿抑心肌再灌注模型 透化的体外制剂的生物化学测量 心肌 将在开胸猪的LAD床上诱发电击 评估局部心肌功能的心脏准备 根据收缩末期压力和 壁厚 单细胞大小的皮肤心肌制备物 将通过机械破坏来自 猪左前降支心肌灌注床。 张力-pCa关系 在这些准备工作中评估将提供一个直接的措施, 肌丝钙敏感性。 我们实验室的初步数据, 该方法显示肌丝Ca 2+敏感性显著降低 在休克心肌中。 这项建议有四个具体目标:(1) 进一步表征体内测量之间的关系, 缺血后机械功能障碍与肌丝的体外测定 同一心脏的Ca 2+敏感性。 正相关意味着 对Ca ~(2+)敏感性降低是心室肌收缩的直接机制, 功能障碍 (2)为了确定肌丝Ca 2+的减少是否 敏感性发生在局部缺血、再灌注或两者期间。 系列措施 对照组、缺血组和缺血后组的肌丝Ca 2+敏感性 从同一心脏获得的顿抑心肌应表明 发生再灌注损伤,并且再灌注损伤是昏迷的独立原因。 的 细胞外钙在再灌注损伤中的作用将被测试, 在体内和体外。 (3)为了确定减少的肌丝是否 Ca 2+敏感性继发于调节蛋白的异常 肌钙蛋白及其亚单位,肌钙蛋白-C、-I和-T。 张力-pCa 提取后比较与顿抑心肌的关系 内源性肌钙蛋白和对照肌钙蛋白替代。 (4)到 评估肌钙蛋白I磷酸化作为一种机制的可能作用 脑缺血后昏迷 因为肌钙蛋白I的磷酸化是一种 肌丝Ca 2+敏感性降低的原因 正常心肌,磷酸酶治疗对张力的影响, 将测量对照和顿抑心肌的pCa关系 和比较 本申请中提出的研究将允许直接 评估肌丝对Ca 2+的敏感性降低, 心肌顿抑的机制,并将提供可能的测试 在肌丝水平和调节水平的击昏机制 proteins.

项目成果

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WILLIAM P MILLER其他文献

WILLIAM P MILLER的其他文献

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{{ truncateString('WILLIAM P MILLER', 18)}}的其他基金

CA++ SENSITIVITY STUNNED IN CARDIAC MYOCYTES
心肌细胞对 CA 的敏感性惊人
  • 批准号:
    2028819
  • 财政年份:
    1993
  • 资助金额:
    $ 18.43万
  • 项目类别:
DECREASED CA++ SENSITIVITY IN STUNNED CARDIAC MYOCYTES
致昏心肌细胞 CA 敏感性降低
  • 批准号:
    2225466
  • 财政年份:
    1993
  • 资助金额:
    $ 18.43万
  • 项目类别:
DECREASED CA++ SENSITIVITY IN STUNNED CARDIAC MYOCYTES
致昏心肌细胞 CA 敏感性降低
  • 批准号:
    2225465
  • 财政年份:
    1993
  • 资助金额:
    $ 18.43万
  • 项目类别:
CA++ SENSITIVITY IN STUNNED CARDIAC MYOCYTES
致昏心肌细胞对 CA 的敏感性
  • 批准号:
    2735211
  • 财政年份:
    1993
  • 资助金额:
    $ 18.43万
  • 项目类别:

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    1988
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