Dependence of fibrinolytic activity on the concentration of free rather than total tissue-type plasminogen activator in plasma after pharmacologic administration.
Dependence of fibrinolytic activity on the concentration of free rather than total tissue-type plasminogen activator in plasma after pharmacologic administration.
复制标题
药物给药后，纤溶活性依赖于血浆中游离而不是总组织型纤溶酶原激活剂的浓度。
DOI：
10.1161/01.cir.79.6.1204
复制
发表时间：
1989
期刊：
影响因子：
37.8
通讯作者：
Sobel,BE
中科院分区：
文献类型：
--
作者：
Lucore,CL;Fujii,S;Sobel,BE
为了确定导致我们在输注激活剂后观察到的血浆组织型纤溶酶原激活剂 (t-PA) 特异性活性下降的因素，并确定选定的 t-PA 变体在梗塞患者中消除这些活性的潜在用途，对来自给予 t-PA 的患者 (n = 4) 和兔子 (n = 15) 的系列血浆样本进行了总 t-PA 抗原、t-PA 活性和游离（与1 型纤溶酶原激活剂抑制剂 (PAI-1)——复合 t-PA。在患者中，输注后 t-PA 比活性明显减弱，总 t-PA 抗原浓度比治疗前值高出七倍（62 ng/ml 与 9 ng/ml 相比）。 t-PA 活性的减弱与血浆中游离 t-PA 的消失相对应，并且与 t-PA 与 PAI-1 复合物的持续存在有关。在通过推注注射野生型 t-PA 的正常兔子 (n = 4) 中，PAI-1 活性为 4 +/- 1 任意单位/ml。 t-PA 活性的减弱直到注射后 60 分钟才明显，此时血浆总 t-PA 抗原浓度低至 13 +/- 8 ng/ml。在这些条件下，血浆 t-PA 主要由游离 t-PA 组成。在给予脂多糖以将血浆 PAI-1 活性增加至 193 +/- 84 任意单位/ml 的兔子 (n = 5) 中，t-PA 的比活性早在注射后 15 分钟就减弱，此时总 t-PA 抗原浓度高达 164 +/- 79 ng/ml。与来自患者的样本的情况一样，衰减与游离 t-PA 的消失以及 t-PA 与 PAI-1 复合物的持续存在有关。 t-PA 的基因工程变体具有与 PAI-1 相当的比活性和相当的速率常数，但设计为在循环中持续存在，表现出从正常兔子 (n = 3) 血浆中的长时间清除（与野生型 t-PA 的 α 相 t1/2 为 1.9 分钟相比，t1/2 = 24.6 +/- 1.6 分钟）。该变体缺乏表皮生长因子和 kringle one 结构域，并包含重复的 kringle 二结构域。（摘要截断为 400 字）
To identify factors responsible for the decline of plasma tissue-type plasminogen activator (t-PA)-specific activity that we have observed after infusions of the activator and to define the potential usefulness of selected variants of t-PA in obviating them in patients with infarction, serial plasma samples from patients (n = 4) and rabbits (n = 15) given t-PA were assayed for total t-PA antigen, t-PA activity, and free as opposed to type-1 plasminogen activator inhibitor (PAI-1)--complexed t-PA. In patients, attenuation of t-PA specific activity after infusions was evident with concentrations of total t-PA antigen that were as much as sevenfold greater than pretreatment values (62 compared with 9 ng/ml). Attenuation of t-PA activity corresponded with the disappearance of free t-PA from plasma and was associated with persistence of complexes of t-PA with PAI-1. In normal rabbits (n = 4) given wild-type t-PA by bolus injection, PAI-1 activity was 4 +/- 1 arbitrary units/ml. Attenuation of t-PA activity was not evident until 60 minutes after injection at a time when total plasma t-PA antigen concentration was as low as 13 +/- 8 ng/ml. Under these conditions, plasma t-PA was composed predominantly of free t-PA. In rabbits (n = 5) given lipopolysaccharide to increase plasma PAI-1 activity to 193 +/- 84 arbitrary units/ml, the specific activity of t-PA was attenuated as early as 15 minutes after injection at a time when total t-PA antigen concentration was as high as 164 +/- 79 ng/ml. As was the case with samples from patients, attenuation was associated with the disappearance of free t-PA and the persistence of complexes of t-PA with PAI-1. A genetically engineered variant of t-PA with comparable specific activity and a comparable rate constant of association with PAI-1 but designed to persist in the circulation manifested prolonged clearance from plasma of normal rabbits (n = 3) (t1/2 = 24.6 +/- 1.6 minutes compared with an alpha phase t1/2 of 1.9 minutes for wild-type t-PA). The variant lacked the epidermal growth factor and kringle one domains and contained a duplicated kringle two domain.(ABSTRACT TRUNCATED AT 400 WORDS)