ALTERED CALCIUM HANDLING IN HYPERTENSIVE HEART DISEASE

描述：（改编自研究者摘要）：拟定的 研究旨在回答这个问题：“细胞机制是什么 负责收缩力的变化与 高血压性心脏病？"心脏肥大的流行观点， 心力衰竭描述了观察到的[Ca] i处理异常， 收缩性降低和钙离子进入的进行性解偶联， 肌浆网（SR）钙释放。 初步数据和文献数据 支持另一种观点，即轻度至中度肥大与 具有增强的收缩力，其终末期肥大和衰竭是 与收缩力下降有关。 总的假设是， [Ca] i处理的异常是增益改变的结果， 钙进入和钙释放之间的关系。 目标1将检验轻度 中度肥大与增强的收缩力有关， 增加钙进入和SR钙释放之间的增益，而严重肥大 和衰竭与收缩性降低和增益降低有关。 逆转肥大和预防衰竭的假设是 依赖于纠正全身性高血压，仅在 还将测试以增加的增益为特征的疾病。 目的2 在整个细胞和单通道水平测试是否ICa，触发 对于SR Ca释放，在肥大和衰竭中不变。 增益将 根据[Ca] i瞬变（全细胞和局部）和L型Ca 电压钳位心室电流（全细胞和单通道） 细胞和测量力，[Ca] i瞬变在完整的小梁。 这 该提案将提供有关改变的细胞机制的见解。 高血压性心脏病的收缩力，结合（1）新概念 （2）新的实验方法（1和2光子激光 扫描共聚焦显微镜），和（3）纵向研究的 肥大的发展及其进展到失败的相关 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.