Enhanced Cholinergic Activity Improves Cerebral Blood Flow during Orthostatic Stress

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.

Keywords: autonomic; cerebral blood flow; cholinergic; orthostasis; orthostatic intolerance.

Figures

Figure 1

Protocol diagram for physostigmine, neostigmine, saline infusion. Protocol for each study session. Participants underwent four tilts consisting of 10 min supine, 5 min tilt, and 5 min recovery. Following each recovery period, infusion was started or increased (every 20 min). Participants were randomly assigned to drug condition, and infusions were performed in a double-blind fashion. Infusion doses are shown for each drug condition (neostigmine and physostigmine) and placebo control (saline).

Figure 2

Cardiovascular response to tilt during physostigmine, neostigmine, and saline infusion. Changes in mean cerebral flow velocity for both arteries (CFV), blood pressure corrected to brain level (BPbrain), and heart rate (HR) from supine (mean of 6–10 min) to 60° head up tilt during infusion of saline (white), neostigmine (gray), or physostigmine (black) at Baseline (no infusion), Dose 1, and Dose 2. *A significant difference from baseline supine values (P < 0.05). †Significantly lower CFV while upright compared to Tilt 1 for saline and neostigmine only (P < 0.05). αSignificant effect of drug at that dose (P < 0.05). All tilt values were significantly different from supine (P < 0.005).

Figure 3

Non-autoregulatory response to infusion. The non-autoregulatory cerebrovascular resistance (CVRNA), blood pressure corrected to brain level (BPbrain), and end-tidal CO2 (PETCO2) response to 5 min of 60° head up tilt during infusion of saline (white), neostigmine (gray), or physostigmine (black) at Baseline, Dose 1, and Dose 2. †Significantly higher CVRNA while upright compared to Tilt 1 for saline and neostigmine only (P < 0.05). αIndicates significant effect of drug at that dose (P < 0.05).

Figure 4

Regional cerebral blood flow response to infusion. Anterior cerebral artery (ACA) and middle cerebral artery (MCA) cerebral flow velocity (CFV) response during 5 min of 60° head up tilt during saline infusion and during Dose 1 and Dose 2 infusion of either neostigmine or physostigmine. There were no significant differences between arteries in responses to either dosage or drug. *A significant difference from baseline tilt values (P < 0.05). αSignificant effect of drug at that dose (P < 0.05).

Figure 5

Regional cerebral blood flow response to infusion during last minute of tilt. Anterior cerebral artery (ACA) and middle cerebral artery (MCA) cerebral flow velocity (CFV) response during last minute of 5 min of 60° head up tilt during saline infusion and during Dose 1 and Dose 2 infusion of either neostigmine or physostigmine. There were no significant differences between arteries in responses to either dosage or drug. αSignificant effect of drug at that dose (P < 0.05).