BLOOD VOLUME AND VENOUS RETURN IN THERMAL STRAIN

这项续签提案的总体目标是揭示 这是等离子体体积膨胀的基础。我们开发了两个模型来研究 这些机制。我们的人体模型，包括32分钟的高强度运动， 在接下来的24小时内产生10%的血浆体积和白蛋白膨胀 我们的动物模型，包括大鼠低血压出血，产生了一个 在24小时内完全恢复容量和白蛋白。 人类和动物模型在某些方面有所不同， 其中两个足够相似，以允许我们生成和测试 然后进行更具侵入性的实验来揭示 大鼠体内的作用机制。 使用人体模型，我们将检验以下假设：i)坠落 大强度运动后中心静脉压和/或平均动脉压 是启动导致血浆升高的事件的主要信号 白蛋白含量。二)血浆白蛋白初始(1-2小时)升高 剧烈运动后的内容是间质起源的， 随后(24小时)血浆白蛋白含量的升高是由于 肝白蛋白合成率。III)急性白蛋白扩张不是 足以在24小时后扩大血浆容量 大强度运动后白蛋白逃逸率降低。 使用动物模型，我们将检验以下假设：i) 白蛋白合成增加在接下来的几个小时内开始 大出血。二)出血后白蛋白合成增加是由于 肝组织白蛋白基因转录增加。三)肝脏增加 出血后白蛋白mRNA转录是由神经启动的 通过卸载心肺和/或动脉产生的信号 压力感受器。四)某些盐分和水分保留荷尔蒙会引起 在分离的、灌流的肝脏白蛋白mRNA转录增加 肝脏制剂。V)增加的白蛋白含量的一部分 出血是由于经毛细血管逃逸速度的降低。 白蛋白。 我们对血浆白蛋白潜在机制的研究 人类运动后恢复过程中的合成和体内的出血 体外和体内动物模型将提供对这种机制的洞察 基础卷恢复。这样的知识将导致发展 更有效地扩大受影响个人的数量的方法 不需要输血。我们对人类和动物模型的使用 允许对既相关又机械的假设进行测试。

The overall aim of this renewal proposal is to uncover the mechanisms that underlie plasma volume expansion. We have developed two models to study these mechanisms. Our human model, involving 32 min of intense exercise, produces a 10% plasma volume and albumin expansion within the following 24 h. Our animal model, involving hypotensive hemorrhage in rats, produces a complete recovery of both volume and albumin within 24 h. Although the human and animal models differ from each other in certain respects, the two are sufficiently analogous to permit us to generate and test hypotheses in humans and then perform more invasive experiments to uncover mechanisms in rats. Using the human model, we will test the following hypotheses: i) the fall in central venous and/or mean arterial pressure following intense exercise are the primary signals that initiate events leading to increased plasma albumin content. ii) an initial (1-2 h) elevation in plasma albumin content after intense exercise is of interstitial origin and the subsequent (24 h) elevation in plasma albumin content is due to increased hepatic albumin synthetic rate. iii) acute albumin expansion is not sufficient to expand the plasma volume after 24 h. iv) the transcapillary escape rate of albumin is decreased after intense exercise. Using the animal model, we will test the following hypotheses: i) increased albumin synthesis is initiated within hours following hemorrhage. ii) increased albumin synthesis following hemorrhage is due to increased hepatic albumin mRNA transcription. iii) increased hepatic albumin mRNA transcription following hemorrhage is initiated by neural signals generated by unloading cardiopulmonary and/or arterial baroreceptors. iv) certain of the salt and water retention hormones cause increased hepatic albumin mRNA transcription in an isolated, perfused liver preparation. v) a portion of the increased albumin content following hemorrhage is due to a reduction in the transcapillary escape rate of albumin. Our studies characterizing the mechanisms underlying plasma albumin synthesis during recovery from exercise in humans and hemorrhage in in vitro and in vivo animal models will provide insight into the mechanisms underlying volume restoration. Such knowledge will lead to the development of methods to volume-expand compromised individuals more effectively without transfusion. Our employment of both human and animal models enables the testing of hypotheses that are both relevant and mechanistic.