Glial Alkalinization Detected In Vivo by 1H‐15N Heteronuclear Multiple‐Quantum Coherence‐Transfer NMR in Severely Hyperammonemic Rat

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Abstract
Brain [5‐15N]glutamine amide protons were selectively observed in vivo by 1H‐15N heteronuclear multiple‐quantum coherence‐transfer NMR in spontaneously breathing, severely hyperammonemic rats during intravenous [15N]ammonium acetate infusion and the subsequent recovery period. The linewidth of brain [5‐15N]‐glutamine amide proton Hz increased from 36 ± 2 Hz at 3.4 h to 58 ± 6 Hz after 5.7 h of infusion, a net increase of 22 ± 6 Hz. Concomitantly, brain ammonia concentration increased from 1.7 to 3.5 ± 0.2 µmol/g and the rat progressed from grade III to grade IV encephalopathy. On recovery to grade III and decrease of brain ammonia concentration to 1.3 µmol/g, the linewidth returned to 37 ± 2 Hz. In aqueous solution, [5‐15N]glutamine amide proton Hz underwent a 17‐Hz linebroadening when pH was raised from 7.1 to 7.5 at 37°C, due to the increased rate of base‐catalyzed exchange with water proton. Hence, linebroadening is a sensitive measure of changing intracellular pH. The 22‐Hz linebroadening observed in vivo in severely hyperammonemic grade IV rats strongly suggests that the intracellular pH increases from 7.1 to about 7.4–7.5 in astrocytes where glutamine is synthesized and mainly stored. Probable mechanisms for the ammonia‐induced alkalinization and decreased intraglial buffering capacity, as well as implications of the result for pathogenesis of hepatic encephalopathy, are discussed.

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