Modulation of rat brain synaptosomal plasma membrane achieved by atracurium and its metabolite laudanosine

Abstract

Objective: Atracurium besylate and laudanosine cause excitement and seizures when introduced into the central nervous system of laboratory animals. We examined the modulation of lipid-protein interaction in the lipid environment of rat brain synaptosomal plasma membrane (SPM)-bound enzymes as a possible mechanism leading to these effects. Methods: The effect of various concentrations of atracurium besylate and laudanosine, or of varying duration of SPM, on the activity of Na+/K+ stimulated ATPase, Mg2+-stimulated ATPase and 5′-nucleotidase were assessed. The modulation of lipid protein interaction by laudanosine was estimated on the basis of the temperature dependence and cooperative behaviour of Na+/K+-stimulated ATPase. Results: The effect of atracurium besylate or laudanosine on Na+/K+-stimulated ATPase activity was biphasic. Maximal enzyme stimulation appeared at 10−4 M atracurium besylate or 10−8 M laudanosine, and at 30 min of pre-incubation with both drugs. Arrhenius plots of Na+/K+-stimulated ATPase showed a transition temperature of 23.0 ± 1.2 °C in control SPM and shifted to 16.5 ± 0.9 °C (p < 0.01) in SPM treated with 10−8 M laudanosine. The Hill coefficients for the allosteric inhibition of Na+/K+-stimulated ATPase by fluoride decreased from 1.99 ± 0.22 in controls to 1.06 ± 0.11 (p < 0.001) in the presence of 10−8 M laudanosine. Conclusions: Our results suggest that laudanosine, one of the principal metabolites of atracurium besylate, affects nerve cell function in rats through the perturbation of the membrane lipid structure accompanied by SPM-bound enzyme dysfunction.

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