CLINICAL CONCENTRATIONS OF EDROPHONIUM ENHANCE DESENSITIZATION OF THENICOTINIC ACETYLCHOLINE-RECEPTOR

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.