May R C, Kelly R A, Mitch W E
J Clin Invest. 1986 Feb;77(2):614-21. doi: 10.1172/JCI112344.
Metabolic acidosis is associated with enhanced renal ammonia-genesis which is regulated, in part, by glucocorticoids. The interaction between glucocorticoids and chronic metabolic acidosis on nitrogen utilization and muscle protein metabolism is unknown. In rats pair-fed by gavage, we found that chronic acidosis stunted growth and caused a 43% increase in urinary nitrogen and an 87% increase in urinary corticosterone. Net protein degradation in incubated epitrochlearis muscles from chronically acidotic rats was stimulated at all concentrations of insulin from 0 to 10(4) microU/ml. This effect of acidosis persisted despite supplementation of the media with amino acids with or without insulin, indomethacin, and inhibitors of lysosomal thiol cathepsins. Acidosis did not change protein synthesis; hence, the increase in net protein degradation was caused by stimulation of proteolysis. Acidosis did not increase glutamine production in muscle. The protein catabolic effect of acidosis required glucocorticoids; protein degradation was stimulated in muscle of acidotic, adrenalectomized rats only if they were treated with dexamethasone. Moreover, when nonacidotic animals were given 3 micrograms/100 g of body weight dexamethasone twice a day, muscle protein degradation was increased if the muscles were simply incubated in acidified media. We conclude that chronic metabolic acidosis depresses nitrogen utilization and increases glucocorticoid production. The combination of increased glucocorticoids and acidosis stimulates muscle proteolysis but does not affect protein synthesis. These changes in muscle protein metabolism may play a role in the defense against acidosis by providing amino acid nitrogen to support the glutamine production necessary for renal ammoniagenesis.
代谢性酸中毒与肾氨生成增强有关，而肾氨生成部分受糖皮质激素调节。糖皮质激素与慢性代谢性酸中毒对氮利用和肌肉蛋白质代谢的相互作用尚不清楚。在通过灌胃进行配对喂养的大鼠中，我们发现慢性酸中毒会阻碍生长，导致尿氮增加43%，尿皮质酮增加87%。在0至10(4)微单位/毫升的所有胰岛素浓度下，慢性酸中毒大鼠孵育的肱三头肌中的净蛋白质降解均受到刺激。尽管在培养基中添加了氨基酸（无论有无胰岛素）、吲哚美辛和溶酶体硫醇组织蛋白酶抑制剂，酸中毒的这种作用仍然存在。酸中毒并未改变蛋白质合成；因此，净蛋白质降解的增加是由蛋白水解的刺激引起的。酸中毒并未增加肌肉中谷氨酰胺的产生。酸中毒的蛋白质分解代谢作用需要糖皮质激素；仅当用地塞米松治疗时，酸中毒的肾上腺切除大鼠的肌肉中蛋白质降解才会受到刺激。此外，当给非酸中毒动物每天两次给予3微克/100克体重的地塞米松时，如果将肌肉简单地在酸化培养基中孵育，肌肉蛋白质降解会增加。我们得出结论，慢性代谢性酸中毒会降低氮利用并增加糖皮质激素的产生。糖皮质激素增加与酸中毒的联合作用会刺激肌肉蛋白水解，但不影响蛋白质合成。肌肉蛋白质代谢的这些变化可能通过提供氨基酸氮来支持肾氨生成所需的谷氨酰胺产生，从而在抵御酸中毒中发挥作用。
