The kinetics of competitive antagonism by cisatracurium of embryonic and adult nicotinic acetylcholine receptors.

摘要: Competitive antagonists to nicotinic acetylcholine receptors are clinically used as muscle relaxants. Previously, we reported the kinetics of inhibition (in absence acetylcholine) by (+)-tubocurarine and pancuronium on embryonic receptors. Here, examine cisatracurium, a commonly relaxant. Outside-out patches were equilibrated with cisatracurium before application 300 μM acetylcholine. inhibited initial peak current, but decay these currents displayed pronounced biphasic behavior. The IC50 value was 54 ± 2 nM 115 4 for adult receptors, respectively. We designed rapid perfusion system apply or remove various times determined association (embryonic, 3.4 0.4 × 108 M−1 s−1; adult, 1.8 0.3 s−1) dissociation 34 6/s; adult: 13 5/s) rates cisatracurium. Association 2.9- 1.3-fold greater than that pancuronium, Dissociation 6- 16-fold higher These measurements correspond from in Physiologically, interacts antagonist. developed mathematical technique removes effect desensitization 52 9/s; 33 presence data suggest one binding site receptor increases rate antagonist other site. incorporated all into computer simulation comprehensive 11-state Markov model. There excellent agreement (without curve fitting) between simulated experimental currents.