Enhanced Cholinergic Activity Improves Cerebral Blood Flow during Orthostatic Stress.

Jorge M Serrador,Roy Freeman

doi:10.3389/fneur.2017.00103

Abstract

Cerebral blood flow (CBF) and consequently orthostatic tolerance when upright depends on dilation of the cerebral vasculature in the face of reduced perfusion pressure associated with the hydrostatic gradient. However, it is still unclear if cholinergic activation plays a role in this dilation. To determine if enhancing central cholinergic activity with the centrally acting acetylcholinesterase inhibitor, physostigmine would increase CBF when upright compared to the peripherally acting acetylcholinesterase inhibitor, neostigmine, or saline. We performed a randomized double-blind dose-ranging study that took place over 3 days in a hospital-based research lab. Eight healthy controls (six women and two men, mean age, 26 years; range 21–33) were given infusions of physostigmine, neostigmine, or saline on three different days. Five-minute tilts were repeated at baseline (no infusion), Dose 1 (0.2 μg/kg/min physostigmine; 0.1 μg/kg/min neostigmine) and Dose 2 (0.6 μg/kg/min physostigmine or 0.3 μg/kg/min neostigmine), and placebo (0.9% NaCl). Cerebral blood velocity, beat-to-beat blood pressure, and end-tidal CO2 were continuously measured during tilts. Physostigmine (0.6 μg/kg/min) resulted in higher cerebral blood velocity during tilt (90.5 ± 1.5%) than the equivalent neostigmine (85.5 ± 2.6%) or saline (84.8 ± 1.7%) trials (P < 0.05). This increase occurred despite a greater postural hypocapnia, suggesting physostigmine had a direct vasodilatory effect on the cerebral vasculature. Cerebral hypoperfusion induced by repeated tilts was eliminated by infusion of physostigmine not neostigmine. In conclusion, this study provides the first evidence that enhancement of central, not peripheral, cholinergic activity attenuates the physiological decrease in CBF seen during upright tilt. These data support the need for further research to determine if enhancing central cholinergic activity may improve symptoms in patients with symptomatic orthostatic intolerance.

Highlights

Orthostatic intolerance, which includes symptoms of lightheadedness, weakness, dizziness and presyncope, is a consequence of the inability to maintain cerebral perfusion when upright (1)
This work provides the first evidence that increasing central cholinergic activity improves the maintenance of cerebral blood flow (CBF) in the upright posture in healthy participants
These data raise the interesting possibility that use of centrally acting acetylcholinesterase inhibitors may improve symptoms in patients with symptomatic orthostatic intolerance

Summary

Introduction

Orthostatic intolerance, which includes symptoms of lightheadedness, weakness, dizziness and presyncope, is a consequence of the inability to maintain cerebral perfusion when upright (1). While the peripheral vascular responses to orthostatic stress are well characterized, the cerebrovascular response is less clearly understood. The upright posture results in a reduction in cerebral perfusion pressure due to the hydrostatic gradient (2), and cerebral resistance vessels must dilate to maintain cerebral blood flow (CBF). An inadequate dilatory response would impair flow. Healthy individuals that develop orthostatic intolerance demonstrate greater decreases in CBF (3, 4), even when arterial pressure is maintained (4), suggesting cerebral vasoconstriction or inadequate cerebral vasodilation is present. The role of cerebral hypoperfusion in orthostatic intolerance patients of diverse causes remains unclear. Some studies have demonstrated greater decreases in CBF (3, 5) while others have not (6)

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Conclusion