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Uncoupling effects of local anesthetics on rat liver mitochondria.

We demonstrate in this paper that bupivacaine, a local anesthetic, can act alone as an uncoupler of rat liver mitochondria. It stimulates state 4 respiration, induces a swelling in potassium acetate (in the presence of valinomycin), and collapses the transmembrane potential. Lidocaine, another local anesthetic, requires the presence of a lipophilic anion such as TPB− to produce the same effects. TPB− can also reinforce the action of bupivacaine. These differences in action of the two local anesthetics can be explained by the difference in their liposolubility.

Epidemiology of traumatic comas: a prospective population-based study.

Objective : Most studies on patients with severe brain injury (SBI) are based on data from specialized centres. This prospective epidemiologic study included all patients in a defined region with a coma lasting more than 24 hours or leading to a death. Methods : All patients with a SBI admitted to an emergency department in the region were included during a 1-year period. A data form was completed with initial neurological state, CT scan lesions and associated injuries. Outcome at the end of acute hospitalization was assessed from medical notes. Results : Two hundred and forty-eight patients were registered. Annual incidence was 8.5/100 000 population. Median age was 41 years. Traffic crashes were the most frequent cause (59%). Falls occurred in 30% (16% from a high level, 14% from one level). Initial GCS was above 8 in 31%, and patients with a neurological deterioration were older (52 vs 32 years). Death occurred in 52% of the cohort. Outcome was related to CT scan diagnosis, delay before eye opening and delay before obeying commands. Conclusion. This population-based cohort of patients with SBI was different from patients selected in trauma centres. The patients were older, more often injured in falls and their mortality rate remained very high.

Effects of bupivacaine on cellular oxygen consumption and adenine nucleotide metabolism.

Previous studies on isolated mitochondria have shown an alteration of mitochondrial metabolism by local anesthetics, with an inhibition of adenosine triphosphate synthesis. To show that the same is true for mitochondria intracellularly the effects of the local anesthetic bupivacaine on cellular energy metabolism were studied on cultured fibroblasts. Cells in suspension were analyzed for oxygen consumption using a polarographic method with a Clark electrode, and for cytosol and mitochondrial adenine nucleotides by high performance liquid chromatography, Bupivacaine produced a dose‐dependent inhibition of oxygen consumption (50% inhibition at 1.5 mM). After incubation in the presence of bupivacaine, adenosine triphosphate and total adenine nucleotides decreased in the cells, as did the adenylate energy charge. These results demonstrate that bupivacaine interacts with cellular energy metabolism and leads to a depletion of high‐energy phosphates. Such intracellular mechanisms could explain in part bupivacaine‐induced myocardial depression.

Mécanismes moléculaires de l'action des anesthésiques locaux

Abstract The main target of local anaesthetics on nervous tissue is the sodium channel. Molecular biology and electrophysiology have shown different mechanisms of action on this sodium channel, which depend on the chemical structure and electrostatic charge of the local anaesthetic molecule. There are two main types of action, shown up on the isolated axon, a direct one on the sodium channel itself and an alteration in the lipids surrounding the channel. These effects have been shown on the isolated axon and explain the anaesthetic effect by an inhibition of the sodium current. Experimental studies have also shown the effects of local anaesthetics on different organelles within the cell, and so on intracellular metabolism. Mitochondrial energetic metabolism, and therefore ATP synthesis, is reduced by local anaesthetics at several levels. The respiratory enzyme chain is inhibited by small concentrations of local anaesthetic, especially NADH dehydrogenase and ubiquinone succinate dehydrogenase. Moreover, local anaesthetics increase the mitochondrial membrane permeability to protons, thus removing the moving force behind ATPase activity in ATP synthesis ; this leads to a drastic fall in available energy. This effect is further increased by a direct inhibition of ATPase and ATP/ADP translocation. Other enzyme systems of other organelles are also disturbed by local anaesthetics, such as the endoplasmic reticular Ca ++ ATPase, which is inhibited, so altering the calcium concentration within the cytosol. Local anaesthetics also inhibit lipolysis and glycogenesis. Receptors such as the acetylcholine receptors are blocked by local anaesthetics. The mechanism of action of these drugs on all these protein systems is two-fold : an alteration of protein structure, but also of the lipids surrounding them. Local anaesthetics should therefore not be considered as acting only on sodium channels, but rather as non specific, disturbing soluble or membrane proteins, and lipids, and so acting on various key enzyme systems. These alterations, especially in cardiac tissue and at the synapse, could explain local anaesthetic toxicity.