Activation of brain acetylcholine receptors by neuromuscular blocking drugs. A possible mechanism of neurotoxicity.
BACKGROUND
Neuromuscular blocking drugs cause excitement and seizures when introduced into the central nervous system. We examined the possibility that these drugs produce paradoxical activation of acetylcholine or glutamate receptors, the chief types of brain receptors involved in excitatory neurotransmission.


METHODS
Because activation of central glutamate or acetylcholine receptors causes calcium influx into postsynaptic neurons, we measured intracellular calcium concentration ([Ca2+]i) as an index of receptor activation. Changes in [Ca2+]i were compared in brain slices exposed to neuromuscular blocking drugs or acetylcholine and glutamate receptor agonists. [Ca2+]i was measured with the fluorescent dye fura-2.


RESULTS
Pancuronium and vecuronium caused sustained increases in [Ca2+]i in approximately the same potency ratio as for seizure activity in vivo (concentrations at which the increase in [Ca2+]i was 95% of maximal: 100 and 400 microM, respectively). Atracurium and laudanosine did not increase [Ca2+]i in cortical slices. Increases in [Ca2+]i caused by both pancuronium and vecuronium were prevented by the non-subtype-specific nicotinic acetylcholine receptor antagonist D-tubocurarine and were reduced 44-73% by atropine. Blockade of glutamate receptors or voltage-gated calcium or sodium channels had no effect on calcium influx.


CONCLUSIONS
The results suggest that the acute excitement and seizures caused by introduction of pancuronium and vecuronium into the central nervous system is due to accumulation of cytosolic calcium caused by sustained activation of acetylcholine receptor ion channels.
Cardone
C
C
Department of Anesthesia, University of California at San Francisco Medical Center 94143-0542.
Szenohradszky
J
J
Yost
S
S
Bickler
P E
PE
D000109:Acetylcholine / Q000494:pharmacology; D000768:Anesthesia, General; D000818:Animals; D001279:Atracurium / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003292:Convulsants / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004737:Enflurane; D005260:Female; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D003473:Neuromuscular Nondepolarizing Agents / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D009538:Nicotine / Q000494:pharmacology; D010197:Pancuronium / Q000633:toxicity*; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014403:Tubocurarine / Q000633:toxicity; D014673:Vecuronium Bromide / Q000633:toxicity
D003292:Convulsants; D005971:Glutamates; D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D009498:Neurotoxins; D011978:Receptors, Nicotinic; D001279:Atracurium; D018698:Glutamic Acid; D010672:Phenytoin; D016202:N-Methylaspartate; D009538:Nicotine; D014673:Vecuronium Bromide; D004737:Enflurane; C001522:laudanosine; D010197:Pancuronium; D000109:Acetylcholine; D007608:Kainic Acid; D002118:Calcium; D014403:Tubocurarine