Cerebral blood flow regulation during acute increases in blood pressure: Can cerebral sympathetic nervous activity act as a gatekeeper?

对熟睡羔羊的研究表明，在动脉血压短暂升高期间，大脑中的交感神经活动（SNA）有可能充当大脑微循环的看门人。然而，在人类中，脑SNA的升高是否会减弱短暂性动脉血压升高期间的脑血流变化仍有待明确确定。此外，动脉二氧化碳和脑代谢通常会在与动脉血压短暂升高相关的生理条件下发生变化，这反过来会影响对脑循环的交感神经控制。当动脉血压急剧升高时，需要考虑这些关键的脑血流决定因素，以分离脑SNA对脑血流调节的作用。我建议使用基于去甲肾上腺素溢出的区域方法来确定脑SNA在动脉血压短暂升高中的作用。本研究计划的总体目的是研究脑SNA在动脉血压短暂升高时对脑血流量的调节作用。具体目的1：为了直接量化在动脉血压短暂升高期间不受低碳酸血症影响的脑SNA的变化，我们将测量单侧等长握力和双腿等长伸展时脑去甲肾上腺素溢出，并将末位二氧化碳分压固定在基线值。然后，为了检验脑SNA是否会减弱短暂性动脉血压升高时脑血流量的变化，我们将使用上述模型测量脑去甲肾上腺素溢出，同时在药物上阻断短暂性动脉血压升高时交感神经活动。特定目的2：为了研究脑代谢是否减弱脑SNA对短暂性动脉血压升高时脑血流变化的影响，我们将测量静息和运动强度增加时输注α -1肾上腺素受体激动剂苯肾上腺素时脑去甲肾上腺素溢出、脑血流量和代谢，并将尾波二氧化碳分压固定在基线值。尽管先前的研究表明，在动脉血压短暂升高时，整体SNA对脑血管起着看门人的作用，但当动脉血压急剧升高时，脑SNA的升高是否会减弱脑血流变化，尚未在完整的人类中得到明确证明。这一建议是直接量化和检查脑SNA在与动脉血压短暂升高相关的生理条件下对人脑血流量的特定作用的关键里程碑。

Research in sleeping lambs suggests that the sympathetic nervous activity (SNA) in the brain has the potential to act as a gatekeeper for the cerebral microcirculation during transient increases in arterial blood pressure. However, whether an elevation in cerebral SNA attenuates cerebral blood flow changes during transient increases in arterial blood pressure remains to be clearly determined in humans. In addition, arterial carbon dioxide and cerebral metabolism will often change in physiological conditions associated with transient increases in arterial blood pressure, which will in turn influence the sympathetic control of the brain circulation. These key cerebral blood flow determinants need to be taken into account to isolate the role of cerebral SNA on cerebral blood flow regulation when arterial blood pressure acutely increases. I propose to identify the role of cerebral SNA during transient increases in arterial blood pressure using a regional approach based on norepinephrine spillover. The overall aim of this research program is to examine the role of cerebral SNA in the regulation of cerebral blood flow during transient increases in arterial blood pressure. SPECIFIC AIM 1: To directly quantify the change in cerebral SNA without the influence of hypocapnia during transient increases in arterial blood pressure, we will measure brain norepinephrine spillover during unilateral isometric handgrip and double leg isometric extension, with end-tidal carbon dioxide partial pressure clamped at baseline value. Then, to examine whether cerebral SNA attenuates the change in cerebral blood flow during transient increases in arterial blood pressure, we will measure brain norepinephrine spillover while pharmacologically blocking sympathetic nerves activity during transient increases in arterial blood pressure using the above-mentioned models. SPECIFIC AIM 2: To examine whether cerebral metabolism attenuates the impact of cerebral SNA on the change in cerebral blood flow during transient increases in arterial blood pressure, we will measure brain norepinephrine spillover, cerebral blood flow and metabolism during infusion of alpha-1 adrenoceptor agonist phenylephrine at rest and during exercise of increasing intensity, with end-tidal carbon dioxide partial pressure clamped at baseline value. Although previous research suggested that global SNA has a gatekeeper role for the brain vessels during transient increases in arterial blood pressure, whether an elevation in cerebral SNA attenuates cerebral blood flow changes when arterial blood pressure acutely increases has not been clearly demonstrated in intact humans. This proposal is a key milestone towards the direct quantification and examination of the specific role of cerebral SNA on human brain blood flow during physiological conditions associated with transient elevations in arterial blood pressure.