Role of Erythrocytes in Circulatory Control

红细胞在循环控制中的作用

• 批准号: 6399104
• 负责人: RANDY SPRAGUE
• 金额: $ 21.9万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6399104
• 关键词: G protein; adenosine triphosphate; erythrocytes; hemodynamics; human subject; laboratory rabbit; nitric oxide; phlebotomy; pulmonary circulation; vascular endothelium; vascular resistance; vascular smooth muscle; vasomotion

When traversing microvascular beds, such as in the lung, red blood cells (RBCs) are subjected to mechanical deformation. Our previous findings that RBCs are required for flow-induced nitric oxide (NO) synthesis in the lung and that mechanical deformation of RBCs results in the release of adenosine triphosphate (ATP), a stimulus for endothelial NO synthesis, suggested a novel mechanism for the control of vascular resistance in the pulmonary circulation. In this construct, as the RBC is increasingly deformed by increments in the velocity of blood flow through a vessel and/or by reductions in vascular caliber, it releases ATP which stimulates endothelial NO synthesis. The abluminal release of NO results in relaxation of vascular smooth muscle and, consequently, an increase in vascular caliber. This vasodilation results in a decrease in vascular resistance, and, thereby, a decrease in the stimulus for RBC deformation and ATP release. Thus, in response to RBC-derived ATP, abluminal release of NO would indirectly inhibit deformation-induced ATP release from RBCs via effects on vascular caliber. However, NO is also released into the vascular lumen by the endothelium in response to ATP. Therefore, in addition to effects on vascular caliber, it is possible that NO released into the vascular lumen could interact directly with circulating RBCs to modulate deformation-induced ATP release. Here, we address the hypothesis that: Deformation-induced ATP release from RBCs of rabbits and humans is regulated by nitric oxide via effects on the activity of a heterotrimeric G protein. In this proposal we intend to 1) establish that the effects of NO donors on deformation-induced ATP release from these RBCs are related to the release of NO, itself, 2) demonstrate that the ability of nitric oxide to inhibit ATP release from these RBCs is independent of an effect on RBC deformability per se, 3) demonstrate that nitric oxide inhibits deformation-induced ATP release from these RBCs as the result of inactivation of a heterotrimeric G protein of the Gi subclass and 4) demonstrate that the ability of nitric oxide to inhibit deformation-induced ATP release from RBCs of rabbits and humans is the result of the stimulation of mono-ADP-ribosylation (inactivation) of Gi and that this effect is reversible. The successful completion of the studies described in this proposal will define a new role for circulating RBCs as regulators of vascular resistance. This proposal is the logical extension of our previous work and is consistent with a major focus of our group, namely, characterization of those mechanisms responsible for the control of vascular resistance, and specifically, the role of RBC-derived ATP as a stimulus for endogenous NO synthesis.

当穿越微血管床（例如在肺中）时，红细胞（RBC）会经过机械变形。我们先前的发现，RBC是肺中流动诱导的一氧化物（NO）合成所必需的，而RBC的机械变形导致释放三磷酸腺苷（ATP），这是一种内皮NO合成的刺激，提示了在肺部循环中控制血管抗性的新型机制。在该构建体中，由于RBC越来越多地通过血液流动的速度和/或血管口径减少而逐渐变形，因此它释放出刺激内皮无合成的ATP。无释放的无效释放导致血管平滑肌松弛，因此血管口径增加。这种血管舒张导致血管耐药性降低，从而减少了RBC变形和ATP释放的刺激。因此，在响应RBC衍生的ATP时，NO的空白释放将通过对血管口径的影响间接抑制RBC从RBC释放的ATP释放。然而，内皮响应于ATP也将NO释放到血管腔中。因此，除了对血管口径的影响外，在血管腔中释放的可能性可能直接与循环的RBC相互作用，以调节变形诱导的ATP释放。在这里，我们解决了以下假设：变形诱导的兔子和人类RBC释放ATP释放，通过对异物三聚体G蛋白活性的影响来调节一氧化氮。 In this proposal we intend to 1) establish that the effects of NO donors on deformation-induced ATP release from these RBCs are related to the release of NO, itself, 2) demonstrate that the ability of nitric oxide to inhibit ATP release from these RBCs is independent of an effect on RBC deformability per se, 3) demonstrate that nitric oxide inhibits deformation-induced ATP release from these RBCs as the result of胃肠道亚类的异三聚体G蛋白的失活，4）表明，一氧化氮抑制兔和人类RBC从RBC中释放的ATP释放的能力是刺激单个ADP-核糖基化（灭活）GI和该效果的刺激的结果。该提案中描述的研究的成功完成将定义循环中的RBC作为血管抗性调节剂的新作用。该提议是我们先前工作的逻辑扩展，与我们小组的主要重点一致，即表征那些负责控制血管抗性的机制，特别是RBC衍生的ATP作为内源性无合成的刺激的作用。