Lombardi G, Mannaioni G, Leonardi P, Cherici G, Carlà V, Moroni F
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
J Neural Transm Gen Sect. 1994;97(3):187-96. doi: 10.1007/BF02336140.
The effects of ammonium salts in concentration similar to those found in plasma in course of hepatic encephalopathy (2-4 mM) were studied in brain slices in order to clarify how glutamate synapses are affected by this pathological situation. Electrophysiological (mice cortical wedge preparations) and biochemical techniques (inositol phosphates and cyclic AMP measurements) were used so that the function of both the ionotropic and metabotropic glutamate receptors was evaluated. Ammonium acetate (2-4 mM), but not sodium acetate reduced the degree of depolarization of cortical wedges induced by different concentrations of N-methyl-D-aspartic acid (NMDA) or (S)-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). This reduction was non-competitive in nature and did not reverse during the experimental period (90 min). In a similar manner, ammonium acetate reduced the formation of inositol phosphates induced by (1S,3R)-1-amynocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (100 microM), the prototype agonist of metabotropic glutamate receptors. When the metabotropic glutamate receptors negatively linked to the forskolin-stimulated cyclic AMP formation were evaluated, ammonium acetate significantly hampered forskolin effects and its actions were additive with those of the metabotropic glutamate receptor agonist 1S,3R-ACPD. In conclusion, our results suggest that toxic concentrations of ammonium impair the function of glutamate receptors of NMDA and AMPA type and of the metabotropic glutamate receptors linked to inositol phosphate formation while they functionally potentiate the action of glutamate agonists on the receptors negatively linked to adenylyl cyclase.
为了阐明谷氨酸能突触在肝性脑病过程中是如何受到这种病理状况影响的，研究了浓度与肝性脑病患者血浆中相似（2-4 mM）的铵盐对脑片的作用。采用了电生理学方法（小鼠皮质楔形标本）和生化技术（肌醇磷酸和环磷酸腺苷测量）来评估离子型和代谢型谷氨酸受体的功能。醋酸铵（2-4 mM）而非醋酸钠降低了不同浓度的N-甲基-D-天冬氨酸（NMDA）或（S）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）诱导的皮质楔形标本的去极化程度。这种降低本质上是非竞争性的，并且在实验期间（90分钟）没有逆转。同样，醋酸铵减少了由（1S,3R）-1-氨基环戊烷-1,3-二羧酸（1S,3R-ACPD）（100 microM）诱导的肌醇磷酸的形成，1S,3R-ACPD是代谢型谷氨酸受体的原型激动剂。当评估与福司可林刺激的环磷酸腺苷形成负相关的代谢型谷氨酸受体时，醋酸铵显著阻碍了福司可林的作用，并且其作用与代谢型谷氨酸受体激动剂1S,3R-ACPD的作用相加。总之，我们的结果表明，毒性浓度的铵会损害NMDA型和AMPA型谷氨酸受体以及与肌醇磷酸形成相关的代谢型谷氨酸受体的功能，而在功能上会增强谷氨酸激动剂对与腺苷酸环化酶负相关的受体的作用。
