MEDIATORS OF CONTRACTILE FAILURE DURING CARDIAC ISCHEMIA

本提案的总体目标是确定 导致急性低血流心肌收缩衰竭 缺血具体而言，这项建议旨在确定 细胞内游离钙（[Ca2 +] i）、无机 磷酸盐（[P-i] i）、酸中毒（（H +] i）、游离镁（[Mg2 +] i），以及 血管压力介导缺血性收缩功能障碍。 健康相关性：低流量缺血性收缩衰竭频繁 导致冠状动脉狭窄患者充血性心力衰竭 疾病阐明这种收缩失败的机制将有助于 发展治疗方式，以减少 低流量缺血的后果。 实验设计：将进行灌注大鼠心脏研究，以i） 证实[Ca2 +] i降低不是缺血性收缩的原因 功能障碍; ii）定量定义[Ca2 +] i-压力关系 在分级的冠状动脉血流减少期间的整个心脏中;以及iii）检查 缺血性收缩功能障碍潜在介质的作用 通过它们对[Ca2 +] i-压力关系的影响。 方法：采用Indo-1荧光法测定[Ca~（2+）] i，采用~（31）P-NMR 测定灌流大鼠心脏中的[P-i] i、[H +] i和[Mg 2 +] i。的 [Ca2+] i-压力关系将在 控制条件和分级冠状动脉血流减少。相应 [P-i] i、[H +] i、（Mg 2 +] i和血管压在改变血管张力中的作用 [Ca2+]将定量检查i-压力关系， 每一个都是独立变量。额外的荧光和NMR 技术将用于确认调查结果。最后，定义技术 将开发开胸猪中的[Ca2 +] i-压力关系， 确定先前体内灌注心脏发现的相关性。

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.