Comparison of the effects of ammonia on brain mitochondrial function in rats and gulf toadfish.

We compared the effect of hyperammonemia on NADH levels in brain slices and on the rate of oxygen consumption from isolated nonsynaptic brain mitochondria in ammonia-sensitive Wistar rats with that in ammonia-tolerant gulf toadfish (Opsanus beta). The NADH content was significantly decreased (12% less than control after 45 min with 1 mM NH(4)Cl) in rat brain slices, but it was not affected in brain slices from toadfish (with both 1 and 6 mM NH(4)Cl). The rates of oxygen consumption of different sets of enzymes of the electron transport chain (ETC; complexes I, II, III, and IV; II, III, and IV; and IV alone) were unaltered by hyperammonemic conditions in isolated nonsynaptic mitochondria from either rats or toadfish. These results lead us to conclude that the differing effects of ammonia on NADH levels in rat and toadfish brain slices must be due to aspects other than the direct effects of ammonia on enzymes of the ETC. Additionally, because these effects were seen in vitro, our studies enabled us to rule out the possibility that effects of ammonia on metabolism were via indirect systemic effects. These results are discussed in the context of current views on mechanisms of central nervous system damage in hyperammonemic states.

[1]  Walsh,et al.  High ammonia tolerance in fishes of the family Batrachoididae (Toadfish and Midshipmen). , 2000, Aquatic toxicology.

[2]  A. Hazell,et al.  Hepatic Encephalopathy: An Update of Pathophysiologic Mechanisms (44433A) , 1999, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[3]  R. Koehler,et al.  Preserved hypocapnic pial arteriolar constriction during hyperammonemia by glutamine synthetase inhibition. , 1999, American journal of physiology. Heart and circulatory physiology.

[4]  Thomas J. Sick,et al.  Calcium Influx from the Extracellular Space Promotes NADH Hyperoxidation and Electrical Dysfunction after Anoxia in Hippocampal Slices , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  T. Sick,et al.  Antioxidants, mitochondrial hyperoxidation and electrical recovery after anoxia in hippocampal slices , 1997, Brain Research.

[6]  R. Koehler,et al.  Methionine Sulfoximine, a Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity during Acute Hyperammonemia , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  R. Koehler,et al.  Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis. , 1996, Stroke.

[8]  T. Sick,et al.  Mitochondrial Hyperoxidation Signals Residual Intracellular Dysfunction after Global Ischemia in Rat Neocortex , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  V. Felipo,et al.  Chronic hyperammonemia prevents changes in brain energy and ammonia metabolites induced by acute ammonium intoxication. , 1993, Biochimica et biophysica acta.

[10]  R. Koehler,et al.  Restoration of cerebrovascular CO2 responsivity by glutamine synthesis inhibition in hyperammonemic rats. , 1992, Circulation research.

[11]  R. Koehler,et al.  Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. , 1991, The American journal of physiology.

[12]  F. Plum,et al.  Biochemistry and physiology of brain ammonia. , 1987, Physiological reviews.

[13]  J. Lai,et al.  Brain α‐Ketoglutarate Dehydrogenase Complex: Kinetic Properties, Regional Distribution, and Effects of Inhibitors , 1986, Journal of neurochemistry.

[14]  N. Cruz,et al.  Cerebral Ammonia Metabolism in Hyperammonemic Rats , 1985, Journal of neurochemistry.

[15]  Arthur J. L. Cooper,et al.  Use of β‐Methylene‐D,L‐Aspartate to Assess the Role of Aspartate Aminotransferase in Cerebral Oxidative Metabolism , 1983, Journal of neurochemistry.

[16]  P. Mensi,et al.  Ammonia toxicity mechanism in fish: studies on rainbow trout (Salmo gairdneri Rich). , 1981, Ecotoxicology and environmental safety.

[17]  M. Norenberg,et al.  Glutamine synthetase: glial localization in brain , 1977, Science.

[18]  M. Norenberg.  A light and electron microscopic study of experimental portal-systemic (ammonia) encephalopathy. Progression and reversal of the disorder. , 1977, Laboratory investigation; a journal of technical methods and pathology.

[19]  R. C. Nielsen,et al.  The acute action of ammonia on rat brain metabolism in vivo. , 1973, The Biochemical journal.

[20]  F. Jöbsis,et al.  Intracellular redox changes in functioning cerebral cortex. I. Metabolic effects of epileptiform activity. , 1971, Journal of neurophysiology.

[21]  B. Siesjö,et al.  The effect of ammonia on the energy metabolism of the rat brain. , 1970, Life sciences. Pt. 2: Biochemistry, general and molecular biology.

[22]  R. Estabrook,et al.  Fluorometric measurement of reduced pyridine nucleotide in cellular and subcellular particles. , 1962, Analytical biochemistry.

[23]  Nathan O. Kaplan,et al.  Fluorescence of Pyridine Nucleotides in Mitochondria , 1962 .

[24]  R. Butterworth.  Glutamate transporter and receptor function in disorders of ammonia metabolism. , 2001, Mental retardation and developmental disabilities research reviews.

[25]  S. Chew,et al.  Ammonia toxicity, tolerance, and excretion , 2001 .

[26]  V. Felipo,et al.  Effects of acute hyperammonemia in vivo on oxidative metabolism in nonsynaptic rat brain mitochondria. , 1997, Metabolic brain disease.

[27]  J. Albrecht,et al.  Astrocyte-neuron interactions in hyperammonemia and hepatic encephalopathy. , 1994, Advances in experimental medicine and biology.

[28]  C. Lee,et al.  Intact Rat Brain Mitochondria from a Single Animal: Preparation and Properties , 1993 .

[29]  T. Sick,et al.  Measurement of Metabolic Activity Associated with Ion Shifts , 1988 .