UNCOUPLING EFFECTS OF DICLOFENAC AND ASPIRIN IN THE PERFUSED LIVER AND ISOLATED HEPATIC MITOCHONDRIA OF RAT

Gluconeogenesis, glycolysis and glycogenolysis were studied in rat per fused liver following the infusion of various concentrations of diclof enac and aspirin, two non-steroidal anti-inflammatory drugs (NSAIDs). Glucose synthesis was measured in livers isolated from 48-h fasted rat s perfused with Krebs-Henseleit bicarbonate buffer containing L-lactat e (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 gluconeogenesi s (GNG). The inhibition was dose-dependent and reversible. For the est imation of glycogenolysis and glycolysis, the rates of glucose release and of lactate and pyruvate production were measured in livers of wel l-fed rats perfused with substrate-free buffer. Infusion of diclofenac (0.1 mM) or aspirin (5 mM) strongly stimulated glycogenolysis and gly colysis (GGL/GL). Ln general, an increased oxygen consumption by the l iver tissue was also noted in both types of experiments, as deduced fr om the continuous monitoring of oxygen concentration changes in the ef fluent. Such a pattern of response can be attributed to the uncoupling effects of the two drugs on oxidative phosphorylation. Measurements o f respiration rates and membrane potential in isolated liver mitochond ria submitted to various concentrations of diclofenac and aspirin conf irms this assumption. Thus, 0.01 to 0.2 mM diclofenac stimulates state -4 respiration and slightly inhibits state 3, decreasing the respirato ry control ratio, while the membrane potential is decreased or collaps ed (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 concent rations of the drugs used largely correspond to the pharmacological do ses employed in antipyretic and anti-inflammatory treatments. Therefor e, a greater consideration should be given to the uncoupling effect, a t least from the toxicological viewpoint.