ALTERED CALCIUM HANDLING IN HYPERTENSIVE HEART DISEASE

描述：(改编自《调查员摘要》)： 研究的目的是回答这样一个问题：细胞机制是什么？ 对与以下相关的收缩能力的改变负责 高血压性心脏病？心脏肥厚的流行观点 心力衰竭描述在[Ca]i处理过程中观察到的异常 钙离子内流和钙离子进行性解偶联的条件 肌浆网(SR)钙释放。初步数据和文献数据 支持另一种观点，即轻度至中度肥厚与 随着收缩能力的增强，终末期肥大和衰竭 与收缩能力下降有关。总体假设是 [Ca]i处理的异常是增益变化的结果 钙进入和钙释放之间的关系。目标1将测试温和的假设 中度肥厚与增强的收缩能力和 钙进入和肌浆网钙释放之间的增量增加，而严重的肥厚 而失败则与收缩能力降低和增益降低有关。 逆转肥厚和预防衰竭的假说是 仅依赖于纠正系统性高血压 这种以增益增加为特征的疾病也将得到测试。目标2 测试在整个小区和单通道级别是否触发ICA、 对于肌浆网钙的释放，在肥厚和衰竭时没有变化。收益将是 由[Ca]i瞬变(全细胞和局部)和L型病例确定 电压钳制心室肌的电流(全细胞和单通道) 通过测量力，在完整的小梁中，[Ca]i瞬变。这 该提案将提供关于改变的细胞机制的见解 结合(1)新概念在高血压性心脏病中的收缩能力 局部控制，(2)新的实验方法(单光子和双光子激光 扫描共聚焦显微镜)，以及(3)纵向研究 肥厚的发展和进展到失败的相关 实验模型。

DESCRIPTION: (Adapted from the Investigator's Abstract)): The proposed research aims to answer the question: "What are the cellular mechanisms responsible for the alterations in contractility associated with hypertensive heart disease?" The prevailing view of cardiac hypertrophy and heart failure describes the observed abnormalities in [Ca]i handling in terms of decreased contractility and progressive uncoupling of Ca entry and sarcoplasmic reticulum (SR) Ca release. Preliminary and literature data support the alternative view that mild to moderate hypertrophy is associated with enhanced contractility which end stage hypertrophy and failure is associated with decreased contractility. The overall hypothesis is that abnormalities in [Ca]i handling are a consequence of alterations in the gain between Ca entry and Ca release. Aim 1 will test the hypothesis that mild to moderate hypertrophy is associated with enhanced contractility and increased gain between Ca entry and SR Ca release whereas severe hypertrophy and failure are associated with decreased contractility and decreased gain. The hypothesis that reversal of hypertrophy and prevention of failure is dependent on correction of systemic hypertension only during the stage of the disease characterized by increased gain also will be tested. Aim 2 tests at the whole cell and single channel level whether ICa, the trigger for SR Ca release, is unaltered in hypertrophy and failure. Gain will be determined from the [Ca]i transients (whole cell and local) and L-type Ca currents (whole cell and single channel) in voltage clamped ventricular cells and by measuring force, [Ca]i transients in intact trabeculae. This proposal will provide insights regarding the cellular mechanisms of altered contractility in hypertensive heart disease by combining (1) the new concept of local control, (2) new experimental methodologies (1 and 2 photon laser scanning confocal microscopy), and (3) the longitudinal study of the development of hypertrophy and its progression to failure in a relevant experimental model.