Cs. Yost et E. Maestrone, CLINICAL CONCENTRATIONS OF EDROPHONIUM ENHANCE DESENSITIZATION OF THENICOTINIC ACETYLCHOLINE-RECEPTOR, Anesthesia and analgesia, 78(3), 1994, pp. 520-526
The principal acetylcholinesterase inhibitors used in clinical practic
e, edrophonium, neostigmine, and pyridostigmine, differ in their abili
ties to reverse profound neuromuscular block. This difference may refl
ect differential inhibition of the nicotinic acetylcholine receptor (n
AChR) itself. To investigate this possibility, we studied the effects
of these drugs on the function of nAChR (alpha(2) beta gamma delta sub
type expressed in Xenopus laevis oocytes) using a whole-cell voltage c
lamp technique. All three drugs produced concentration-dependent inhib
ition of nAChR currents induced by the nicotinic agonist dimethylpheny
l piperazinium iodide (DMPP). However, only with edrophonium did the e
ffective inhibitory concentration overlap with the clinical range, pro
ducing 47% inhibition of nAChR current at the peak serum concentration
(60 mu M) obtained from a 1 mg/kg dose. The inhibition by edrophonium
was voltage-dependent, being more potent at hyperpolarized membrane p
otentials [IC50(-60 mV) = 82.1 +/- 5.0 mu M; IC50(-90 mV) = 50.8 +/- 2
.7 mu M; IC50(-120 mV) = 41.1 +/- 1.3 mu M] and implying some degree o
f channel block within the ion-conducting pore. Edrophonium also enhan
ced desensitization of the nAChR within the clinically observed range.
Edrophonium desensitization of the nAChR was further increased by sim
ultaneous exposure to other drugs known to promote desensitization of
the receptor. These two mechanisms, channel block and enhanced desensi
tization, may provide molecular explanations for the lesser capacity o
f edrophonium to promote complete reversal of profound neuromuscular b
lock.