MODULATION OF RAT-BRAIN SYNAPTOSOMAL PLASMA-MEMBRANE ACHIEVED BY ATRACURIUM AND ITS METABOLITE LAUDANOSINE

Objective: Atracurium besylate and laudanosine cause excitement and se izures when introduced into the central nervous system of laboratory a nimals. We examined the modulation of lipid-protein interaction in the lipid environment of rat brain synaptosomal plasma membrane (SPM)-bou nd enzymes as a possible mechanism leading to these effects. Methods: The effect of various concentrations of atracurium besylate and laudan osine, or of varying duration of SPM, on the activity of Na+/K+ stimul ated ATPase, Mg2+-stimulated ATPase and 5'-nucleotidase were assessed. The modulation of lipid protein interaction by laudanosine was estima ted on the basis of the temperature dependence and cooperative behavio ur of Na+/K+ stimulated ATPase.Results: The effect of atracurium besyl ate 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 temp erature of 23.0 +/- 1.2 degrees C in control SPM and shifted to 16.5 /- 0.9 degrees C (p < 0.01) in SPM treated with 10(-8) M laudanosine, The Hill coefficients for the allosteric inhibition of Na+/K+-stimulat ed 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. Conclus ions: Our results suggest that laudanosine, one of the principal metab olites of atracurium besylate, affects nerve cell function in rats thr ough the perturbation of the membrane lipid structure accompanied by S PM-bound enzyme dysfunction.