MEDIATORS OF CONTRACTILE FAILURE DURING CARDIAC ISCHEMIA

这项提案的总体目标是确定机制 急性低流量心肌收缩衰竭的原因分析 缺血症。具体地说，这项建议旨在确定 细胞内游离钙([Ca~(2+)]i)、无机的各自作用 磷酸盐([P-I]I)、酸中毒((H+]I)、游离镁([Mg2+]I)以及 血管压力在介导缺血性收缩功能障碍中的作用。 与健康相关：经常出现低流量缺血性收缩衰竭 冠状动脉患者发生充血性心力衰竭的结果 疾病。阐明这种收缩功能衰竭的机制将有助于 减少疾病的治疗方法的发展 低流量缺血的后果。 实验设计：灌流大鼠心脏研究将进行至I) 确认[Ca~(2+)]i降低不是缺血性收缩的原因 功能障碍；ii)定量定义[Ca~(2+)]i-压力关系 在分级冠状动脉血流减少期间的全心脏；以及iii)检查 缺血性收缩功能障碍的潜在介质作用 通过它们对[Ca~(2+)]i-压力关系的影响。 方法：采用Indo-1荧光法测定[Ca~(2+)]i和~(31)P-核磁共振 测定灌流大鼠心脏的[P-i]i、[H+]i和[Mg2+]i。这个 [Ca2+]i-压力关系将在 控制条件和分级冠脉流量减少。各自的 [P-i]i、[H+]i、(mg2+)i和血管压力在改变血管内皮细胞功能中的作用 将定量检测[Ca2+]i-压力关系，分离 每一项都作为一个自变量。附加荧光和核磁共振 技术将被用来证实发现。最后，定义 开胸猪的[Ca~(2+)]i-压力关系将发展为 确定之前的活体心脏灌流发现的相关性。

The overall goal of this proposal is to determine the mechanisms responsible for the myocardial contractile failure of acute low flow ischemia. Specifically, this proposal is designed to ascertain the respective roles of intracellular free calcium ([Ca2+]i), inorganic phosphate ([P-i]i), acidosis ((H+]i), free magnesium ([Mg2+]i), and vascular pressure in mediating ischemic contractile dysfunction. Health Relatedness: Low flow ischemic contractile failure frequently results in congestive heart failure in patients with coronary artery disease. Elucidating the mechanisms of this contractile failure will aid the development of therapeutic modalities to reduce the morbid consequences of low flow ischemia. Experimental Design: Perfused rat heart studies will be performed to i) verify that decreased [Ca2+]i is not responsible for ischemic contractile dysfunction; ii) quantitatively define the [Ca2+]i-pressure relationship in whole hearts during graded coronary flow reductions; and iii) examine the role of potential mediators of ischemic contractile dysfunction through their effect on the [Ca2+]i-pressure relationship. Methods: Indo-1 fluorescence will be used to measure [Ca2+]i, and 31P-NMR to measure [P-i]i, [H+]i, and [Mg2+]i, in perfused rat hearts. The [Ca2+]i-pressure relationship will be quantitatively defined during control conditions and graded coronary flow reductions. The respective roles of [P-i]i, [H+]i, (Mg2+]i, and vascular pressure in altering the [Ca2+]i-pressure relationship will be examined quantitatively, isolating each as an independent variable. Additional fluorescence and NMR techniques will be used to confirm findings. Finally, techniques to define the [Ca2+]i-pressure relationship in open-chest pigs will be developed to determine the relevance of the previous perfused heart findings in vivo.