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 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+-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.

• Authors: E F Kamper, J Siafaka, J Stavridis
• Journal: Intensive care medicine (Intensive Care Med) Vol. 24 Issue 5 Pg. 519-25 (May 1998) ISSN: 0342-4642 [Print] United States
• PMID: 9660270 (Publication Type: Journal Article)

Chemical References

• Central Nervous System Agents
• Isoquinolines
• Neuromuscular Depolarizing Agents
• Atracurium
• laudanosine
• 5'-Nucleotidase
• Ca(2+) Mg(2+)-ATPase
• Sodium-Potassium-Exchanging ATPase

Topics

• 5'-Nucleotidase (drug effects)
• Animals
• Atracurium (pharmacology)
• Brain (drug effects, enzymology)
• Ca(2+) Mg(2+)-ATPase (drug effects)
• Cell Membrane (drug effects, enzymology)
• Central Nervous System Agents (pharmacology)
• Dose-Response Relationship, Drug
• Isoquinolines (pharmacology)
• Male
• Neuromuscular Depolarizing Agents (pharmacology)
• Rats
• Rats, Wistar
• Sodium-Potassium-Exchanging ATPase (drug effects)
• Synaptosomes (drug effects, enzymology)