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

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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.