ERYTHROCYTES AND CIRCULATORY CONTROL

红细胞和循环控制

• 批准号: 2609322
• 负责人: RANDY SPRAGUE
• 金额: $ 18.09万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-15 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2609322
• 关键词: adenosine triphosphate; chloride channels; dogs; eicosanoid metabolism; erythrocytes; hemodynamics; human subject; laboratory rabbit; nitric oxide; paracrine; phlebotomy; pulmonary circulation; vascular endothelium; vascular resistance; vascular smooth muscle; vasomotion

DESCRIPTION (Modified from the applicant): It is well established that nitric oxide (NO), is produced by endothelial cells and is capable of relaxing vascular smooth muscle. Alterations in shear stress have been suggested to be a major stimulus for NO release from the endothelium. A reappraisal of this viewpoint was required, however, when the investigators found that in the rabbit pulmonary circulation, in the absence of red blood cells (RBCs), alterations in shear stress alone did not evoke NO release. Therefore, it was concluded that, in the pulmonary circulation, an interaction, not related to shear stress, occurs between the RBC and the endothelium resulting in NO synthesis. In the present study it is hypothesized that the RBC releases a mediator that, in turn, stimulates NO synthesis, affecting, thereby, local hemodynamic changes. It is postulated that the mediator released is adenosine triphosphate (ATP) and that an important stimulus for the release of ATP is mechanical deformation of the RBC. In the present proposal the aims are to 1) characterize the contribution of the RBC and ATP to vascular caliber in the intact lung, 2) determine that mechanical deformation of the RBC is a stimulus for the release of ATP from that cell, 3) establish that RBC-derived ATP results in endothelial NO synthesis, 4) demonstrate that the mechanism by which ATP is released from the RBC in response to mechanical deformation is via the activity of the cystic fibrosis transmembrane conductance regulator and 5) establish that NO released into the vascular lumen alters RBC deformability leading to reduced ATP release. The thesis that mechanical deformation of RBCs leads to ATP release which, in turn, stimulates NO synthesis suggests a novel and important mechanism for the local control of vascular caliber. In this construct, the RBC is increasingly deformed by increments in blood flow through a vessel of constant or decreasing radius or by reductions in vascular caliber at constant or increasing flow. In response to deformation, ATP is released from the RBC which stimulates NO synthesis by endothelial cells. The abluminal release of NO results in relaxation of vascular smooth muscle leading, ultimately, to a decrease in the stimulus for RBC deformation, thereby, limiting the stimulus for ATP release and NO synthesis. In addition, NO released into the vascular lumen interacts with the RBC leading to increased deformablity and reduced ATP release, again limiting the stimulus for ATP release. This hypothesis is the logical progression of previous work and is consistent with a major focus of this group, namely identification and characterization of those mechanisms responsible for the control of vascular resistance.

描述（根据申请人进行修改）：已确定 一氧化氮（NO）由内皮细胞产生，能够 轻松的血管平滑肌。 剪切应力的改变已经 建议是不释放内皮的主要刺激。 一个 但是，当调查人员需要重新评估该观点 发现在没有红血的兔子肺循环中 细胞（RBC），仅剪切应力的改变并未引起均未释放。 因此，得出的结论是，在肺循环中 与剪切应力无关的相互作用发生在RBC和 内皮导致无合成。 在本研究中是 假设RBC释放了一个介质，而介质又刺激了否 合成，影响局部血流动力学变化。 它是假定的 释放的介体是三磷酸腺苷（ATP）， 释放ATP的重要刺激是机械变形 RBC。 在本提议中，目的是1）表征 RBC和ATP对完整肺的血管口径的贡献，2） 确定RBC的机械变形是对 从该单元中释放ATP，3）确定RBC衍生的ATP导致 内皮NO合成，4）证明ATP的机制 从RBC响应机械变形而释放的是 囊性纤维化跨膜电导调节器的活性和5） 确定没有释放到血管腔内改变RBC的可变形性 导致ATP释放减少。 论点的机械变形 RBC会导致ATP释放，从而刺激NO合成表明A 局部控制血管口径的新颖和重要机制。 在 这种结构，RBC越来越多地通过血流的增量变形 通过半径恒定或减小的容器或减少 血管口径在恒定或增加流量下。 响应 变形，ATP从RBC释放 内皮细胞。 放松的无效释放 血管平滑肌最终导致刺激减少 对于RBC的变形，从而限制了ATP释放的刺激 合成。 此外，没有释放到血管管腔与 RBC导致变形增加并减少ATP释放，再次 限制ATP释放的刺激。 这个假设是合乎逻辑的 以前的工作的发展，与此的重点是一致的 小组，即这些机制的识别和表征 负责控制血管抗性。