Brain Glucose Levels in Portacaval-Shunted Rats with Chronic, Moderate Hyperammonemia: Implications for Determination of Local Cerebral Glucose Utilization

Abstract

Summary: Rates of glucose utilization (lCMRglc) in many structures of the brain of fed, portacaval-shunted rats, when assayed with the [14C]deoxyglucose (DG) method in our laboratory, were previously found to be unchanged (30 of 36 structures) or depressed (6 structures) during the first 4 weeks after shunting, but to rise progressively to higher than normal values in 25 of 36 structures from 4-12 weeks. In contrast, ICMRglc, when assayed with the [14C]glucose method in another laboratory, was de pressed in most structures of brains of 4-8-week shunted rats that had relatively high brain ammonia levels. There was a possibility that the increases in ICMRglc obtained with the [14C]DG method may have been artifactual, due, in part, to a change in brain glucose content which could alter the value of the lumped constant of the DG method. Brain glucose levels of shunted rats were, therefore, as sayed by both direct chemical measurement in freeze blown samples and by determination of steady-state brain:plasma distribution ratios for e4C]methylglucose; Liver disease is accompanied by chronic hyper ammonemia and alterations in behavior and mental state. Ammonia is widely regarded as a toxin with a "threshold level for neurotoxicity" of about 1 j-Lmol/g of brain; above this level EEG abnormalities and behavioral changes (e.g., lethargy, stupor, and coma) are observed in experimental animals Cooper and Plum, 1987;Raabe, 1990). Construction of a portacaval shunt chroni cally elevates ammonia levels in blood and brain,

Organ Distribution of 13N Following Intravenous Injection of [13N]Ammonia into Portacaval-Shunted Rats

“…Previous studies consistently reported sustained, 2–3-fold increases in arterial blood and brain ammonia levels in both awake and N 2 O-sedated (70–75%N 2 O/25–30%O 2 ), paralyzed-ventilated PCS rats, with higher ammonia levels in brain than in blood (e.g., [6, 8–10, 33, 34]). Awake PCS rats exhibit 2–3-fold higher blood and brain ammonia levels than do controls within one week after portacaval shunting, and they remain elevated for at least 14 weeks (Table 1).…”

“…Ammonia levels were not measured in the present study, but blood and brain ammonia levels in the ~12 week PCS rats are anticipated to be elevated by 2.6–3.4-fold and ~3-fold, respectively (Table 1). Note, however, that blood and brain ammonia and glucose concentrations can vary considerably with the procedure used to construct the portacaval shunt, especially at short time intervals following the surgery [8]. Moreover, ammonia levels can have a large impact on physiological and metabolic changes, such as cerebral blood flow and glucose utilization that depend in part on the time after shunting [8].…”

“…Note, however, that blood and brain ammonia and glucose concentrations can vary considerably with the procedure used to construct the portacaval shunt, especially at short time intervals following the surgery [8]. Moreover, ammonia levels can have a large impact on physiological and metabolic changes, such as cerebral blood flow and glucose utilization that depend in part on the time after shunting [8]. Based, in part, on these previous studies 12 weeks was considered sufficient time post-surgery for the animals to adapt metabolically and physiologically to the shunt procedure and to chronic hyperammonemia.…”

“…The concentration of ammonia in the portal vein in normal rats is ~1 mM, and the hepatic extraction efficiency of ammonia from the portal vein is ~100% [11]. Thus, under normal conditions little if any portal vein ammonia enters the general circulation and the liver maintains the level of circulating ammonia at relatively low levels, typically ≤ 100 μM in rats (see Table 6 in [8]) and ≤ 40 μM in humans (reference value for clinical laboratories). Following portacaval shunting, blood draining from the gut bypasses the liver and directly enters the systemic circulation.…”

“…Diversion of ammonia-laden blood from the portal vein into the systemic circulation compounded by liver shrinkage and decreased ability of muscle to remove circulating ammonia, results in a 2–3-fold elevated concentration of ammonia in systemic blood in PCS rats. This, in turn, is associated with chronically-elevated brain ammonia levels after shunt construction [8]. However, it is not known whether long-term hyperammonemia alters the distribution of blood-derived ammonia nitrogen among body organs, and the goal of the present study was to gain some insights into ammonia-derived nitrogen metabolism by assessing uptake of tracer amounts of [ 13 N]ammonia and retention of 13 N in body tissues in PCS rats.…”