Coronary Physiology

描述(申请人提供)：当心率增加时(如运动时)，冠脉血流量必须增加，以向心脏提供氧气，以支持增加的心肌耗氧量。这项研究的目的是发现冠脉血流量与心肌耗氧量之间的基本生理机制。如果没有这些机制，心脏就会变得缺血并死亡。提出了一个新的假说，并提供了支持数据，其中冠脉循环中的红细胞释放的三磷酸腺苷作为局部代谢性冠状动脉血管扩张的中介。提出了一项计划，通过结合ATP测量和ATP受体阻断来定量检验运动、限流和贫血期间的ATP假说。第二个新的假说是，红细胞中的脱氧血红蛋白催化血液中的亚硝酸盐(NO2-)转化为一氧化氮(NO)，从而导致冠状动脉扩张。提出了一项计划，通过亚硝酸盐在运动、限流和贫血时的测量来检验亚硝酸盐到一氧化氮的假说。这一应用的统一概念是，红细胞血红蛋白在冠状动脉血流控制中充当氧气传感器。这两个假说解释了局部代谢负反馈控制冠状动脉血流的机制。当心肌耗氧量增加时，这可以防止心肌缺血。与公众健康相关的是，拟议的基础研究是理解冠状动脉疾病和心肌缺血背后的正常冠状动脉生理的基础。这是RO1 HL 082781-01-A1的重新提交(这一次是模块赠款)。

DESCRIPTION (provided by applicant): When heart rate increases (as occurs during exercise), coronary blood flow must increase to provide oxygen to the heart to support the augmented myocardial oxygen consumption. The purpose of the proposed research is to discover essential physiological mechanisms that couple coronary blood flow to myocardial oxygen consumption. Without these mechanisms, the heart becomes ischemic and dies. A new hypothesis, with supporting data, is presented where ATP released from red blood cells in the coronary circulation acts as a mediator of local metabolic coronary vasodilation. A plan is presented to quantitatively test the ATP hypothesis during exercise, restricted flow, and anemia with a combination of ATP measurements and ATP-receptor blockade. A second new hypothesis, with supporting data, is presented where deoxyhemoglobin in red blood cells catalyzes the conversion of blood nitrite (NO2-) to nitric oxide (NO) that causes coronary vasodilation. A plan is presented to test the nitrite to nitric oxide hypothesis with nitrite measurements during exercise, restricted flow, and anemia. The unifying concept of this application is that red blood cell hemoglobin acts as an oxygen sensor in the control of coronary blood flow. The two hypotheses explain mechanisms responsible for local metabolic negative feedback control of coronary blood flow. This prevents myocardial ischemia whenever there is an increase in myocardial oxygen consumption. The relevance to public health is that the proposed basic research is fundamental to understanding the normal coronary physiology that underlies coronary artery disease and myocardial ischemia. This is a resubmission of RO1 HL 082781-01-A1 (This time as a modular grant.)