Robust Brain Hyperglycemia during General Anesthesia: Relationships with Metabolic Brain Inhibition and Vasodilation

Abstract

Glucose is the main energetic substrate for the metabolic activity of brain cells and its proper delivery into the extracellular space is essential for maintaining normal neural functions. Under physiological conditions, glucose continuously enters the extracellular space from arterial blood via gradient-dependent facilitated diffusion governed by the GLUT-1 transporters. Due to this gradient-dependent mechanism, glucose levels rise in the brain after consumption of glucose-containing foods and drinks. Glucose entry is also accelerated due to local neuronal activation and neuro-vascular coupling, resulting in transient hyperglycemia to prevent any metabolic deficit. Here, we explored another mechanism that is activated during general anesthesia and results in significant brain hyperglycemia. By using enzyme-based glucose biosensors we demonstrate that glucose levels in the nucleus accumbens (NAc) strongly increase after iv injection of Equthesin, a mixture of chloral hydrate and sodium pentobarbital, which is often used for general anesthesia in rats. By combining electrochemical recordings with brain, muscle, and skin temperature monitoring, we show that the gradual increase in brain glucose occurring during the development of general anesthesia tightly correlate with decreases in brain-muscle temperature differentials, suggesting that this rise in glucose is related to metabolic inhibition. While the decreased consumption of glucose by brain cells could contribute to the development of hyperglycemia, an exceptionally strong positive correlation (r = 0.99) between glucose rise and increases in skin-muscle temperature differentials was also found, suggesting the strong vasodilation of cerebral vessels as the primary mechanism for accelerated entry of glucose into brain tissue. Our present data could explain drastic differences in basal glucose levels found in awake and anesthetized animal preparations. They also suggest that glucose entry into brain tissue could be strongly modulated by pharmacological drugs via drug-induced changes in metabolic activity and the tone of cerebral vessels.

Keywords: anesthesia; brain and body hypothermia; metabolic brain inhibition; nucleus accumbens; rats; vasoconstriction; vasodilation.

Figure 1

Graphic representation of data used to determine basal concentrations of extracellular glucose in the NAc. (A) shows the values of basal electrochemical currents detected by active (enzume-containing) and null (enzyme-free) sensors as well as the range of glucose sensitivity (nA/0.5 mM corrected for 37°C) of active sensors. (B) shows the range of differences between active and null currents detected at the same time points. (C) shows the values of basal glucose levels in this sample. See text for more detail explanations.

Figure 2

Mean (± SEM) changes in NAc electrochemical currents (A; orange: glucose and blue: null sensors) and glucose concentration (B) induced by iv injection of Equithesin. Gray area shows the duration of iv injection (0–120 s). Filled symbols in (B) show values significantly different from the pre-injection baseline (p < 0.05).

Figure 3

Original examples of changes in electrochemical currents detected by glucose (A–D) and null (E) sensors following novelty test (A,B,E) and iv injections of Equithesin (C–E). Data were obtained with 1-s time resolution. Gray areas in each graph show the duration of stimulation or injection. Anesthetic drug was delivered at 23 and 37°C.

Figure 4

Mean (± SEM) changes in NAc electrochemical currents (A,C) and resulting change in glucose concentration (B) after iv injection of Equithesin analyzed with slow (2-min bin) and rapid (10-s bin) time resolution. (A,C) show changes detected by active (enzyme-containing) and null (enzyme-free) sensors for 120 min (A) and 8 min (C) after drug administration. Blue and red values show changes with the drug delivered at room (23°C) and body (37°C) temperatures, respectively. Filled symbols in each graph indicate values significantly different from the pre-injection baseline. N is the number of averaged tests.

Figure 5

Changes in different temperature parameters induced by iv injection of Equithesin, shown with slow (A–C; 2-min bin), and rapid (D–F; 10-s bins) time resolutions. The top graphs (A,D) show absolute changes in NAc, temporal muscle, and skin temperatures; middle graphs (B,E) show relative changes in these parameters; and bottom graphs (C,F) show changes in NAc-Muscle and Skin-Muscle temperature differentials. Values significantly different from pre-injection baseline are shown as filled symbols. In (A–C), the moment of injection is shown by a vertical hatched line (0 min) with an arrow; in (D–F), duration of injection (0–120 s) is shown as gray shaded areas. In (F), r is coefficient of correlation determined from 120 to 480 s post injection onset.

Figure 6

Correlative relationships between anesthesia-induced changes in NAc glucose and two primary indices reflecting metabolic activity (NAc-Muscle differential; A,C) and vascular tone (Skin-Muscle differential; B,D) analyzed with slow (A,B) and rapid (C,D) time resolutions. For explanations see the text.

Figure 7

Mean (± SEM) changes in temperatures (A–D), NAc electrochemical currents (E; orange: glucose and blue: null sensors), and glucose concentration (F) induced by the novelty test. The rat at time 0 was introduced to a glass beaker, which was removed from the cage at time 60 s. In (A,B), onset of arousing stimulation is shown as vertical hatched line with arrow and in (C–F), duration of stimulation (0–60 s) is shown as a gray shaded area. Filled symbols in each graph show values significantly different from baseline.