Kawaguchi Tetsu, Brusilow Saul W, Traystman Richard J, Koehler Raymond C
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, 600 North Wolfe St./Blalock 1404-E, Baltimore, MD 21287-4961, USA.
Am J Physiol Regul Integr Comp Physiol. 2005 Jun;288(6):R1612-9. doi: 10.1152/ajpregu.00783.2004. Epub 2005 Feb 10.
Glutamine has been shown to influence endothelial-dependent relaxation and nitric oxide production in vitro, possibly by limiting arginine availability, but its effects in vivo have not been well studied. Hyperammonemia is a pathophysiological condition in which glutamine is elevated and contributes to depressed CO(2) reactivity of cerebral arterioles. We tested the hypothesis that acute hyperammonemia decreases pial arteriolar dilation to acetylcholine in vivo and that this decrease could be prevented by inhibiting glutamine synthetase with L-methionine-S-sulfoximine (MSO) or by intravenous infusion of L-arginine. Pial arteriolar diameter responses to topical superfusion of acetylcholine were measured in anesthetized rats before and at 6 h of infusion of either sodium or ammonium acetate. Ammonium acetate infusion increased plasma ammonia concentration from approximately 30 to approximately 600 microM and increased cerebral glutamine concentration fourfold. Arteriolar dilation to acetylcholine was intact after infusion of sodium acetate in groups pretreated with vehicle or with MSO plus methionine, which was coadministered to prevent MSO-induced seizures. In contrast, dilation in response to acetylcholine was completely blocked in hyperammonemic groups pretreated with vehicle or methionine alone. However, MSO plus methionine administration before hyperammonemia, which maintained cerebral glutamine concentration at control values, preserved acetylcholine dilation. Intravenous infusion of L-arginine during the last 2 h of the ammonium acetate infusion partially restored dilation to acetylcholine without reducing cerebral glutamine accumulation. Superfusion of 1 or 2 mM L-glutamine through the cranial window for 1 h in the absence of hyperammonemia attenuated acetylcholine dilation but had no effect on endothelial-independent dilation to nitroprusside. We conclude that 1) hyperammonemia reduces acetylcholine-evoked dilation in cerebral arterioles, 2) this reduction depends on increased glutamine rather than ammonium ions, and 3) increasing arginine partially overcomes the inhibitory effect of glutamine.
谷氨酰胺已被证明在体外可影响内皮依赖性舒张和一氧化氮生成，可能是通过限制精氨酸的可利用性，但它在体内的作用尚未得到充分研究。高氨血症是一种病理生理状态，其中谷氨酰胺水平升高，并导致脑小动脉的二氧化碳反应性降低。我们检验了以下假设：急性高氨血症会在体内降低软脑膜小动脉对乙酰胆碱的舒张反应，并且这种降低可通过用L-蛋氨酸-S-亚砜胺（MSO）抑制谷氨酰胺合成酶或静脉输注L-精氨酸来预防。在麻醉大鼠中，在输注醋酸钠或醋酸铵之前和输注6小时后，测量软脑膜小动脉直径对局部灌注乙酰胆碱的反应。输注醋酸铵使血浆氨浓度从约30微摩尔/升增加到约600微摩尔/升，并使脑谷氨酰胺浓度增加四倍。在用载体或MSO加蛋氨酸预处理的组中，输注醋酸钠后，小动脉对乙酰胆碱的舒张反应保持完好，蛋氨酸是与MSO共同给药以预防MSO诱导的癫痫发作。相比之下，在用载体或单独蛋氨酸预处理的高氨血症组中，对乙酰胆碱的舒张反应完全被阻断。然而，在高氨血症之前给予MSO加蛋氨酸，可使脑谷氨酰胺浓度维持在对照值，从而保留了乙酰胆碱舒张反应。在醋酸铵输注的最后2小时内静脉输注L-精氨酸，部分恢复了对乙酰胆碱的舒张反应，而没有减少脑谷氨酰胺的积累。在无高氨血症的情况下，通过颅骨窗超灌注1或2毫摩尔/升的L-谷氨酰胺1小时，减弱了乙酰胆碱舒张反应，但对硝普钠引起的非内皮依赖性舒张无影响。我们得出结论：1）高氨血症会降低脑小动脉中乙酰胆碱诱发的舒张反应；2）这种降低取决于谷氨酰胺增加而非铵离子；3）增加精氨酸可部分克服谷氨酰胺的抑制作用。
