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Synergy between pairs of competitive antagonists at adult human muscle acetylcholine receptors.

Abstract：

BACKGROUND:Synergistic neuromuscular blocking effects have been observed clinically with certain pairs of nicotinic acetylcholine receptor (nAChR) competitive antagonists. The mechanism for synergy has not been elucidated. We tested the hypothesis that synergy arises from a differential selectivity of antagonists for the two ligand binding sites on adult human nAChR. METHODS:We expressed nAChR in BOSC23 cells. We applied ACh with or without antagonists to outside-out patches and measured macroscopic currents at room temperature. We determined the IC(90) for (+)-tubocurarine, metocurine, pancuronium, vecuronium, cisatracurium, rocuronium, and atracurium. For 15 combinations of two antagonists, we determined the IC(90) for one antagonist in the presence of the IC(70) of a second antagonist. We constructed isobolograms for 90% inhibition. For single antagonists, we measured inhibition of receptors containing mutations in the epsilon- and delta-subunits to determine site selectivity. RESULTS:Two pairs of antagonists, metocurine+cisatracurium and cisatracurium+ atracurium exhibited additive inhibition. Ten combinations, including (+)-tubocurarine+ pancuronium and pancuronium+vecuronium, were highly synergistic such that the combination was two to three times more effective than expected for additivity. Three combinations were 1.5-1.6 times more effective than expected for additivity. Inhibition by (+)-tubocurarine and metocurine was sensitive to mutations in the epsilon-subunit only. Vecuronium was affected by the delta-subunit mutation only. Inhibition by other antagonists was decreased by mutations in either subunit. CONCLUSIONS:Many combinations of antagonists exhibited synergistic effects on adult human nAChR. Synergy was observed with structurally similar and dissimilar antagonists. The degree of synergy did not always correlate well with site specificity assayed with mutants. In some, but not all cases, the synergy at the receptor level correlated with clinical determinations of synergy. We conclude that the synergistic actions of muscle relaxants can be partially explained by direct interactions with adult human nAChR.

journal_name

Anesth Analg

journal_title

Anesthesia and analgesia

authors

Liu M,Dilger JP

doi

10.1213/ane.0b013e31817b4469

subject

Has Abstract

pub_date

2008-08-01 00:00:00

pages

525-33

issue

eissn

0003-2999

issn

1526-7598

pii

107/2/525

journal_volume

107

pub_type

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Synergy between pairs of competitive antagonists at adult human muscle acetylcholine receptors.