Preuss H G, Roxe D M, Bourke E
Department of Medicine, Georgetown University Medical Center, Washington, DC 20007.
Life Sci. 1987 Oct 5;41(14):1695-702. doi: 10.1016/0024-3205(87)90596-0.
We believe that two findings are interconnected and help to comprehend a major mechanism behind the regulation of renal ammonia production during acidosis. First, slices from acidotic compared to control and alkalotic rats produce more ammonia from glutamine. Second, inhibition of renal oxidative metabolism at various points by metabolic inhibitors augments slice ammoniagenesis. Based on this, our purpose was to determine whether enhanced renal ammoniagenesis during acidosis could occur through the same mechanism as the metabolic inhibitors. However, metabolic inhibitors (malonate; arsenite; 2,4-dinitrophenol) usually decrease while acidosis increases slice gluconeogenesis. There is one known exception. Fluorocitrate, which blocks citrate metabolism, simulates the acidotic condition by enhancing both ammonia and glucose production. Accordingly, a block of oxidative metabolism if located prior to citrate oxidation in the tricarboxylic acid cycle could theoretically augment ammoniagenesis during acidosis. Lactate, is a major renal fuel whose oxidative metabolism would be blocked by fluorocitrate. There, we concentrated on the effects of acidosis on lactate as well as glutamine metabolism. Lactate decarboxylation decreases in the face of increased glucose production during acidosis, and lactate inhibition of glutamine decarboxylation decreases in slices from acidotic rats. Also, we found lesser oxygen consumption in the presence of lactate by kidney slices from acidotic rats compared to control and alkalotic rats. We postulate that relatively less incorporation of lactate into the TCA cycle, causing decreased citrate formation and citrate oxidation during acidosis, contributes, at least in part, to acidotic adaptation of ammoniagenesis.
我们认为有两个发现相互关联，有助于理解酸中毒期间肾脏氨生成调节背后的主要机制。第一，与对照和碱中毒大鼠相比，酸中毒大鼠的切片从谷氨酰胺产生更多的氨。第二，代谢抑制剂在不同点抑制肾脏氧化代谢会增强切片的氨生成。基于此，我们的目的是确定酸中毒期间肾脏氨生成增加是否通过与代谢抑制剂相同的机制发生。然而，代谢抑制剂（丙二酸；亚砷酸盐；2,4-二硝基苯酚）通常会减少，而酸中毒会增加切片的糖异生。有一个已知的例外。氟柠檬酸可阻断柠檬酸代谢，通过增加氨和葡萄糖的生成来模拟酸中毒状态。因此，理论上，如果在三羧酸循环中柠檬酸氧化之前阻断氧化代谢，可能会增强酸中毒期间的氨生成。乳酸是肾脏的主要燃料，其氧化代谢会被氟柠檬酸阻断。因此，我们专注于酸中毒对乳酸以及谷氨酰胺代谢的影响。在酸中毒期间葡萄糖生成增加的情况下，乳酸脱羧减少，并且酸中毒大鼠切片中乳酸对谷氨酰胺脱羧的抑制作用降低。此外，我们发现与对照和碱中毒大鼠相比，酸中毒大鼠的肾切片在有乳酸存在时耗氧量更低。我们推测乳酸相对较少地进入三羧酸循环，导致酸中毒期间柠檬酸形成和柠檬酸氧化减少，这至少部分地促成了氨生成的酸中毒适应性变化。
