NONLINEAR MODELING OF MYOCARDIAL TRANSPORT & ENERGY METABOLISM

心肌转运的非线性建模

• 批准号: 6308548
• 负责人: KEITH KROLL
• 金额: $ 2.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6308548
• 关键词: Mammalia; bioengineering /biomedical engineering; biomedical resource; human tissue; technology /technique

The capillary endothelial enzyme, xanthine oxidase/dehydrogenase, which mediates oxidation of hypoxathine to xanthine, and xanthine to uric acid, was investigated in the perfused beating heart. Intracoronary bolus injections were made of [14C]-hypoxanthine (together with reference tracers [131I]-albumin and [3H]-L-glucose), while measuring venous concentrations of the injected tracers and [14C]-xanthine and [14C]-uric acid, formed in endothelial cells. Sufficient unlabeled carrier hypoxanthine was co-injected that peak concentrations swept through the likely concentration range of the enzyme Km. The dilution curves showed strikingly low levels of coronary efflux of [14C]-xanthine, suggesting very low endothelial membrane permeability. However, the possibility of low permeability had to be discarded as a result of additional experiments in which [14C]-xanthine was injected in the tracer bolus instead of hypoxanthine, and it was observed that the peak extraction of xanthine was nearly as high as that of hypoxanthine (0.5). Fitting the dilution curves using a multiple species nonlinear model of capillary-tissue transport, binding and reaction indicated that prolonged retention of xanthine following hypoxanthine injection was likely due to slow dissociation of the enzyme-xanthine product complex. This appears to favor subsequent reaction to uric acid over release of free xanthine. Consistent with this interpretation was the finding that when [14C]-xanthine was injected in the bolus, there was less formation of end product [14C]-uric acid, than when [14C]-hypoxanthine was injected. Therefore, it seems that the high affinity binding of the enzyme to xanthine serves to insure that most of the hypoxanthine oxidized in the first step of the reaction is not released from the enzyme until it is further oxidized to uric acid in the second step.

毛细血管内皮酶，黄嘌呤氧化酶/脱氢酶， 它将次黄嘌呤氧化为黄嘌呤，并将黄嘌呤氧化为黄嘌呤 尿酸在灌流心脏跳动中的变化。 冠状动脉内团注是由[14C]-次黄嘌呤制成的 (连同参比示踪剂[131I]-白蛋白和[~3H]-L-葡萄糖)， 同时测量注射示踪剂的静脉浓度和 [14C]-黄嘌呤和[14C]-尿酸，在内皮细胞中形成。 将足够未标记载体次黄嘌呤与峰共注入 浓度席卷了可能的浓度范围 酶Km。稀释曲线显示出极低水平的 冠脉流出[14C]-黄嘌呤，提示内皮细胞非常低 膜通透性。然而，低渗透性的可能性 必须丢弃，因为在这些额外的实验中 [14C]-在示踪剂推注中注射黄嘌呤，而不是 次黄嘌呤，并观察到黄嘌呤的峰提取 几乎与次黄嘌呤(0.5)一样高。适合于 稀释度曲线的多组分非线性模型 毛细血管-组织运输、结合和反应表明 次黄嘌呤注射后黄嘌呤滞留时间延长 可能是由于酶-黄嘌呤产物的缓慢解离所致 很复杂。这似乎更有利于尿酸的后续反应。 释放游离黄嘌呤。与这种解释一致的是 发现当[14C]-黄嘌呤注射到团注中时，有 最终产物[14C]-尿酸的形成比 [14C]-注射次黄嘌呤。因此，看起来高 该酶与黄嘌呤的亲和结合可确保大多数 次黄嘌呤在反应的第一步就被氧化了 从酶中释放，直到它被进一步氧化为尿酸 第二步。