Uncoupling effects of diclofenac and aspirin in the perfused liver and isolated hepatic mitochondria of rat

Abstract

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.

Betaine-Palmitate Reduces Acetylsalicylic Acid-induced Gastric Damage in Rats

“…The hypothesis that ATP depletion is primarily responsible for mucosal injury has received much support over the past few years (14,15). After ingestion, ASA is hydrolysed rapidly to salicylate, a potent uncoupler of mitochondrial oxidative phosphorylatio n (4,16). In the present study we provided evidence that the 72-h ASA treatment signi cantly depleted the mucosal ATP stores with a concomitant disruption of the gastric mucosal barrier.…”

Emergency Department Management of the Salicylate-Poisoned Patient

“…As the poisoning progresses and more of the aspirin is absorbed into the serum and is incorporated into the mitochondria, uncoupling oxidative phosphorylation, lactic acid accumulates in the serum, and metabolic compensatory mechanisms are initiated [16]. Hyperventilation becomes a true compensatory mechanism in addition to the byproduct of central medullary stimulation [20].…”

The uncoupling effect of the nonsteroidal anti‐inflammatory drug nimesulide in liver mitochondria from adjuvant‐induced arthritic rats

“…15,16 For the assay of NADH oxidase, intact mitochondria were frozen in liquid nitrogen and thawed rapidly at 37 . This procedure was repeated three times.…”