Kamel K S, Cheema-Dhadli S, Halperin M L
Renal Division, St. Michael's Hospital, University of Toronto, Ont., Canada.
Can J Physiol Pharmacol. 1992 Nov;70(11):1477-82. doi: 10.1139/y92-209.
We examined mechanisms by which dichloroacetate (DCA), an activator of pyruvate dehydrogenase (PDH), led to a decrease in the concentration of lactate in blood in a unique "metabolic setting," where the concentration of lactate in blood was 5.4 +/- 0.5 mmol/L. Elevated levels of lactate were induced in anaesthetized rabbits by the administration of a large dose of insulin. The rate of consumption of oxygen was 1.2 +/- 0.1 mmol/min, the respiratory quotient was close to unity, and close to half of the PDH was in its active form; therefore, virtually all ATP synthesis should require flux through PDH. Hence, we predicted that DCA should not cause a significant decrease in the concentration of lactate in blood in this model. In contrast, if DCA was effective, new insights could be obtained into its mechanisms of action, at least in this setting. During steady-state hyperlactatemia, DCA was given as its sodium salt, 2 mmol/kg (n = 10); a control group (n = 5) received equimolar NaCl. Forty minutes later, the level of lactate in blood in the DCA group was 1.3 +/- 0.2 mmol/L, significantly lower than in the NaCl group (4.2 +/- 0.6 mmol/L). To determine the organ(s) responsible for removing lactate, arteriovenous differences were measured in organs drained by the jugular, femoral, and hepatic veins. There was no net uptake of lactate in these drainage beds after DCA was administered. From a quantitative analysis of the rate of removal of lactate and the rate of consumption of oxygen, it seems unlikely that the majority of the decrease in lactate could be directly attributed to an increase in its oxidation.
我们研究了丙酮酸脱氢酶（PDH）激活剂二氯乙酸（DCA）在一种独特的“代谢环境”中导致血液中乳酸浓度降低的机制，在此环境中血液中乳酸浓度为5.4±0.5 mmol/L。通过给麻醉的兔子注射大剂量胰岛素来诱导乳酸水平升高。氧气消耗速率为1.2±0.1 mmol/分钟，呼吸商接近1，且近一半的PDH处于活性形式；因此，几乎所有ATP合成都应需要通过PDH的通量。因此，我们预测在该模型中DCA不应导致血液中乳酸浓度显著降低。相反，如果DCA有效，则至少在此环境中可以获得关于其作用机制的新见解。在稳态高乳酸血症期间，以2 mmol/kg的钠盐形式给予DCA（n = 10）；对照组（n = 5）接受等摩尔的NaCl。40分钟后，DCA组血液中的乳酸水平为1.3±0.2 mmol/L，显著低于NaCl组（4.2±0.6 mmol/L）。为了确定负责清除乳酸的器官，测量了由颈静脉、股静脉和肝静脉引流的器官的动静脉差异。给予DCA后，这些引流床中没有乳酸的净摄取。从对乳酸清除率和氧气消耗率的定量分析来看，乳酸的大部分降低似乎不太可能直接归因于其氧化增加。
