FLOW AND METABOLIC TRACER KINETICS IN HEART

心脏中的血流和代谢示踪动力学

• 批准号: 6030918
• 负责人: ROBERT C MARSHALL
• 金额: $ 36.28万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030918
• 关键词: bioimaging /biomedical imaging; blood flow measurement; cardiography; computer program /software; deoxyglucose; glucose metabolism; heart metabolism; laboratory rabbit; mathematical model; mitochondria; pharmacokinetics; radionuclide emission tomography; radiotracer

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.

描述（改编自申请人的摘要）：分离的红血 细胞白蛋白灌注兔心脏将用于（1）研究使用 Patlak和Sokoloff方法定量心肌葡萄糖 消耗18F-2-氟-2-脱氧-D-葡萄糖（FDG），和（2）评估 线粒体亲合放射性标记化合物的动力学。 三个项目 旨在调查Patlak使用中的潜在问题， 定量心肌葡萄糖代谢的Sokoloff示踪动力学模型。 在第一个项目中，申请人提出调查潜在的 Patlak的葡萄糖代谢率（GMR）估计不准确 由于FDG之间的非平衡， 血浆和可逆组织隔室。 在第二个项目中，他们 将在延长的洗脱期间评估FDG-6-PO 4的去磷酸化 无FDG灌注液的周期。 在第三个项目中，他们将 研究降低“索科洛夫”号复杂性的可能性 隔室模型，通过测量示踪剂的输送和分布， 多指示剂稀释技术 鱼藤酮及其类似物是 中性亲脂性化合物，其是本发明化合物的复合物1的有效抑制剂， 线粒体电子传递链 申请人综合了 18F-二氢鱼藤酮（FDHR）和125 I-鱼藤酮，并已表明它们具有 在离体兔心中的提取率高、保留时间长。 的 待检验的中心假设是心肌提取和保留 这些放射性标记的鱼藤酮化合物主要依赖于流量， 通过线粒体功能的改变而改变。 罗丹明-123 和99 mTc-Sestamibi在具有止血作用的活性线粒体中积累， 膜电位 在所有拟议的调查中，申请人 建议比较鱼藤酮化合物的提取和保留 罗丹明-123和99 mTc-sestamibi。 他们会评估心肌 提取和保留这些亲脂剂超过 生理相关的流量范围。 同样，改变的效果 恒定流量下的氧化代谢率对心肌动力学的影响 还将研究这些化合物。 最后，氧气的作用 去除鱼藤酮、罗丹明-123和99 mTc-sestamibi提取物， 将对保留进行评估。 在所有关于贪婪的研究中， Sokoloff房室模型和FDG的研究 多指示剂稀释技术和线性、时不变的 脉冲响应模式将用于分析心肌提取， 保留这些痕迹。 使用脉冲的主要优点是 反应模型是可以独立评估循环 分散，间隙扩散，细胞提取和保留 感兴趣的流动或代谢示踪剂。