NONLINEAR MODELING OF MYOCARDIAL TRANSPORT & ENERGY METABOLISM

心肌转运的非线性建模

• 批准号: 6280748
• 负责人: KEITH KROLL
• 金额: $ 8.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-18 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6280748
• 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， 其介导次黄嘌呤氧化为黄嘌呤，黄嘌呤氧化为 尿酸，在灌注跳动的心脏进行了研究。 冠状动脉内推注[14 C]-次黄嘌呤 （与参比示踪剂[131 I]-白蛋白和[3 H]-L-葡萄糖一起）， 同时测量注射的示踪剂的静脉浓度， [14 C]-黄嘌呤和[14 C]-尿酸，在内皮细胞中形成。 共进样足够的未标记载体次黄嘌呤， 浓度扫过可能的浓度范围的 酶Km。稀释曲线显示， [14 C]-黄嘌呤的冠状流出，表明内皮细胞非常低 膜透性 然而，低渗透率的可能性 不得不被丢弃，因为额外的实验， [14 C]-黄嘌呤被注射到示踪剂团中，而不是 次黄嘌呤，并且观察到黄嘌呤的峰提取 几乎与次黄嘌呤一样高（0.5）。 拟合 稀释曲线使用多物种非线性模型， 毛细血管-组织转运、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 复杂. 这似乎有利于随后的反应，尿酸超过 释放游离黄嘌呤。 与这一解释相一致的是 发现当[14 C]-黄嘌呤被注射到药丸中时， 最终产物[14 C]-尿酸的形成比当 注射[14 C]-次黄嘌呤。 因此，似乎高 酶与黄嘌呤的亲和结合用于确保大多数 在反应的第一步中氧化的次黄嘌呤不 从酶中释放出来，直到它被进一步氧化成尿酸， 第二步。