FLOW AND METABOLIC TRACER KINETICS IN HEART

描述(改编自申请者摘要)：分离的红血 细胞白蛋白灌流的兔心将被用于(1)研究其用途 Patlak和Sokoloff心肌葡萄糖定量方法的比较 使用18F-2-氟-2-脱氧-D-葡萄糖(FDG)，以及(2)评估 线粒体亲和性放射性标记化合物的动力学。三个项目是 旨在调查Patlak使用中的潜在问题和 量化心肌葡萄糖代谢的索科洛夫示踪动力学模型。 在第一个项目中，申请者提议调查潜在的 Patlak对葡萄糖代谢率(GMR)估计的不准确 FDG不平衡引起的多次图解分析 血浆和可逆组织隔间。在第二个项目中，他们 将评估FDG-6-PO4在长期洗脱过程中的去磷酸化 使用不含FDG灌流液的时期。在第三个项目中，他们将 研究降低Sokoloff的复杂性的可能性 通过测量示踪剂的传输和分布来建立隔室模型 多指示剂稀释技术。鱼藤酮及其类似物为 中性、亲脂性化合物，是The Complex 1的有效抑制剂 线粒体电子传输链。申请者已经综合了 18F-二氢鱼藤酮(FDHR)和125I-鱼藤酮。 高萃取率和在离体兔心脏中的长期滞留。这个 需要检验的中心假设是心肌提取和滞留 这些放射性标记的鱼藤酮化合物主要依赖于流动， 易受线粒体功能变化的影响。罗丹明-123 和99mTc-Sestamibi在有止血作用的活跃线粒体中蓄积 膜电位。在所有拟议的调查中，申请人 建议比较鱼藤酮类化合物的提取和保留率 罗丹明-123和99mTc-Sestamibi。他们会评估心肌梗死 这些线粒体嗜血剂的提取和保留 生理上相关的流动范围。同样，改变的效果(S) 恒流条件下氧化代谢速率对心肌动力学的影响 这些化合物也将被研究。最后，氧气的影响 剥夺鱼藤酮、罗丹明-123和99mTc-Sestamibi提取液和 将对保留率进行评估。在所有关于线粒体嗜好的研究中 Sokoloff隔室模型和FDG的研究 多指示剂稀释技术与线性时不变 脉冲响应模式将用于分析心肌提取和 保留这些示踪剂。使用脉冲的主要优势是 反应模型是可以独立评估循环的 弥散、间质扩散、细胞提取和保留 感兴趣的流动或代谢示踪剂。

DESCRIPTION (Adapted from Applicant's Abstract): The isolated red blood cell-albumin perfused rabbit heart will be used to (1) investigate the use of the Patlak and Sokoloff methodologies to quantify myocardial glucose consumption with 18F-2-fluoro-2-deoxy-D-glucose (FDG), and (2) evaluate the kinetics of mitochondrial avid radiolabeled compounds. Three projects are designed to investigate potential problems in the use of the Patlak and Sokoloff tracer kinetic models to quantify myocardial glucose metabolism. In the first project, the applicants proposed to investigate potential inaccuracies of glucose metabolic rate (GMR) estimates by the Patlak multiple-time graphical analysis due to non-equilibration of FDG between plasma and reversible tissue compartments. In the second project, they would evaluate dephosphorylation of FDG-6-PO4 during an extended wash-out period with FDG-free perfusate. In the third project, they would investigate the possibility of reducing the complexity of the Sokoloff compartment model by measuring tracer delivery and distribution with the multiple indicator dilution technique. Rotenone and its analogues are neutral, lipophilic compounds that are potent inhibitors of Complex 1 of the mitochondrial electron transport chain. The applicants have synthesized 18F-dihydrorotenone (FDHR) and 125I-rotenone and have shown that they have a high extraction and long retention in the isolated rabbit heart. The central hypothesis to be tested is that myocardial extraction and retention of these radiolabeled rotenone compounds are primarily dependent on flow, subject to modification by changes in mitochondrial function. Rhodamine-123 and 99mTc-sestamibi accumulate in active mitochondria that have hemostatic membrane potentials. In all of proposed investigations, the applicants proposed to compare the extraction and retention of the rotenone compounds to Rhodamine-123 and 99mTc-sestamibi. They would evaluate myocardial extraction and retention of these mitochondrial-avid agents over a physiologically relevant flow range. Similarly, the effect(s) of altered rates of oxidative metabolism at constant flow on myocardial kinetics of these compounds will also be studied. Finally, the effect of oxygen deprivation of rotenone, Rhodamine-123, and 99mTc-sestamibi extraction and retention will be evaluated. In all studies of the mitochondrial-avid agents and in the investigation on the Sokoloff compartment model and FDG the multiple indicator dilution technique and the linear, time-invariant impulse responses mode will be used to analyze myocardial extraction and retention of these tracers. The major advantage of using the impulse response model is that it is possible to independently evaluate circulatory dispersion, interstitial diffusion, and cellular extraction and retention of the flow or metabolic tracer of interest.