Effects of Acute Hyperammonemia on Cerebral Amino Acid Metabolism and pH_i In Vivo, Measured by ¹H and ³¹P Nuclear Magnetic Resonance

Abstract

The effects of an acute intravenous infusion of ammonium acetate on rat cerebral glutamate and glutamine concentrations, energy metabolism, and intracellular pH were measured in vivo with 1H and 31P nuclear magnetic resonance (NMR). The level of blood ammonia maintained by the infusion protocol used in this study (approximately 500 microM, arterial blood) did not cause significant changes in arterial PCO2, PO2, or pH. Cerebral glutamate levels fell to at least 80% of the preinfusion value, whereas glutamine concentrations increased 170% relative to the preinfusion controls. The fall in brain glutamate concentrations followed a time course similar to that of the rise of brain glutamine. There were no detectable changes in the content of phosphocreatine (PCr) or nucleoside triphosphates (NTP), within the brain regions contributing to the sensitive volume of the surface coil, during the ammonia infusion. Intracellular pH, estimated from the chemical shift of the inorganic phosphate resonance relative to the resonance of PCr in the 31P spectrum, was also unchanged during the period of hyperammonemia. 1H spectra, specifically edited to allow quantitation of the brain lactate content, indicated that lactate rose steadily during the ammonia infusion. Detectable increases in brain lactate levels were observed approximately 10 min after the start of the ammonia infusion and by 50 min of infusion had more than doubled. Spectra acquired from rats that received a control infusion of sodium acetate were not different from the spectra acquired prior to the infusion of either ammonium or sodium acetate.(ABSTRACT TRUNCATED AT 250 WORDS)

The Ammonium-Induced Increase in Rat Brain Lactate Concentration is Rapid and Reversible and is Compatible with Trafficking and Signaling Roles for Ammonium

“…We can therefore be confident that glutamate decreased, in agreement with previous reports that hyperammonemia decreases glutamate (Hindfelt and Siesjö , 1971b;O'Connor et al, 1984;Bates et al, 1989;Fitzpatrick et al, 1989;Zwingmann et al, 2003). Quantitatively, the decrease in glutamate concentration would have been somewhat greater than the 7.1% decrease in the peak area.…”

“…It is also known that infusion or injection of quantities of ammonium similar to our infusions does not decrease high-energy phosphates (Hindfelt and Siesjö , 1971b;Hawkins et al, 1973;Fitzpatrick et al, 1989).…”

“…Other reports describe measurements made at one time point after an intraperitoneal injection of ammonium (Hindfelt and Siesjö , 1971b;Hawkins et al, 1973;Hindfelt, 1973;O'Connor et al, 1984), or during a maintained constant concentration in the blood (Fitzpatrick et al, 1989). Acute hyperammonemia increases brain lactate concentration (Hindfelt and Siesjö, 1971b;Hawkins et al, 1973;O'Connor et al, 1984;Fitzpatrick et al, 1989), but it is not known whether this indication of increased glycolysis has a rapid onset nor whether it reverses rapidly: these are necessary conditions if ammonium is to be considered as a candidate physiological signal. As a first step toward testing this, we have made new kinds of measurements, with improved time resolution, of changes induced by brief (4 mins) intravenous infusions of ammonium.…”

The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by 1-Observed, 13C-Edited NMR Spectroscopy

“…The surface coil, and 8 x 12-mm single-turn ellipse, was tuned to the frequencies of two nuclei simultaneously: lH and 13C or lH and 3lp, as described previously (den Hol lander et al, 1984;Behar et al, 1985). An estimate of the depth and lateral extent of the volume of rat brain tissue detected by the surface coil for the pulse sequence and acquisition parameters used to obtain lH and 3lp spectra in this study has been reported (Fitzpatrick et al, 1989).…”

“…IH spectra were acquired alternately with 3lp spectra to monitor the effects of the glucose infusions on the total concentration of brain glu tamate and glutamine (see Fitzpatrick et al, 1989). These animals (n = 4) received an infusion of unlabeled [1 2 C]glucose identical to those receiving [13C]glucose.…”