Petrescu I, Tarba C
Department of Animal Physiology, Babes-Bolyai University, Cluj-Napoca, Romania.
Biochim Biophys Acta. 1997 Feb 15;1318(3):385-94. doi: 10.1016/s0005-2728(96)00109-0.
Gluconeogenesis, glycolysis and glycogenolysis were studied in rat perfused liver following the infusion of various concentrations of diclofenac and aspirin, two non-steroidal anti-inflammatory drugs (NSAIDs). Glucose synthesis was measured in livers isolated from 48-h fasted rats perfused with Krebs-Henseleit bicarbonate buffer containing L-lactate (2 mM) and pyruvate (0.1 mM) as precursors. Both diclofenac (0.01-0.1 mM) and aspirin (1-10 mM) had an inhibitory effect on gluconeogenesis (GNG). The inhibition was dose-dependent and reversible. For the estimation of glycogenolysis and glycolysis, the rates of glucose release and of lactate and pyruvate production were measured in livers of well-fed rats perfused with substrate-free buffer. Infusion of diclofenac (0.1 mM) or aspirin (5 mM) strongly stimulated glycogenolysis and glycolysis (GGL/GL). In general, an increased oxygen consumption by the liver tissue was also noted in both types of experiments, as deduced from the continuous monitoring of oxygen concentration changes in the effluent. Such a pattern of response can be attributed to the uncoupling effects of the two drugs on oxidative phosphorylation. Measurements of respiration rates and membrane potential in isolated liver mitochondria submitted to various concentrations of diclofenac and aspirin confirms this assumption. Thus, 0.01 to 0.2 mM diclofenac stimulates state-4 respiration and slightly inhibits state 3, decreasing the respiratory control ratio, while the membrane potential is decreased or collapsed (depending on the drug concentration). Similar effects are recorded for aspirin at higher concentrations (0.2-5 mM), even though state 3 is not affected in this case. Arguments are presented that the concentrations of the drugs used largely correspond to the pharmacological doses employed in antipyretic and anti-inflammatory treatments. Therefore, a greater consideration should be given to the uncoupling effect, at least from the toxicological viewpoint.
在灌注大鼠肝脏中，研究了两种非甾体抗炎药（NSAIDs）——双氯芬酸和阿司匹林在输注不同浓度后的糖异生、糖酵解和糖原分解情况。在从禁食48小时的大鼠分离出的肝脏中，用含有L-乳酸（2 mM）和丙酮酸（0.1 mM）作为前体的Krebs-Henseleit碳酸氢盐缓冲液进行灌注，测量葡萄糖合成。双氯芬酸（0.01 - 0.1 mM）和阿司匹林（1 - 10 mM）均对糖异生（GNG）有抑制作用。这种抑制作用呈剂量依赖性且可逆。为了评估糖原分解和糖酵解，在灌注无底物缓冲液的饱食大鼠肝脏中测量葡萄糖释放速率以及乳酸和丙酮酸生成速率。输注双氯芬酸（0.1 mM）或阿司匹林（5 mM）强烈刺激糖原分解和糖酵解（GGL/GL）。一般来说，在这两种类型的实验中，从流出物中氧气浓度变化的连续监测推断，肝脏组织的耗氧量也增加。这种反应模式可归因于这两种药物对氧化磷酸化的解偶联作用。对暴露于不同浓度双氯芬酸和阿司匹林的分离肝脏线粒体进行呼吸速率和膜电位测量证实了这一假设。因此，0.01至0.2 mM双氯芬酸刺激状态4呼吸并轻微抑制状态3，降低呼吸控制率，而膜电位降低或崩溃（取决于药物浓度）。对于较高浓度（0.2 - 5 mM）的阿司匹林也记录到类似效应，尽管在这种情况下状态3不受影响。有观点认为，所使用的药物浓度在很大程度上对应于解热和抗炎治疗中使用的药理剂量。因此，至少从毒理学角度来看，应更多地考虑解偶联效应。
