The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors

We studied the inhibition of fetal (gamma-nAChR) and adult (epsilon-nAChR) muscle-type nicotinic acetylcholine receptors by the two new nondepolarizing muscle relaxants (NDMRs) rocuronium and rapacuronium, the metabolite 3-desacetyl rapacuronium (Org 9488), and five other, longer-used NDMRs (pancuronium, vecuronium, mivacurium, d-tubocurarine, and gallamine). Receptors were expressed in Xenopus laevis oocytes by cytoplasmic injection of subunit complementary RNAs. Functional channels were activated with 10 microM acetylcholine, alone or in combination with various concentrations of the NDMRs. Currents were recorded with a whole-cell two-electrode voltage clamp technique. All NDMRs reversibly inhibited acetylcholine-activated currents in a dose-dependent fashion. Potencies of rapacuronium and Org 9488 were not statistically different at either gamma-nAChR (half-maximal response = 58.2 and 36.5 nM, respectively) or epsilon-nAChR (half-maximal response = 80.3 and 97.7 nM, respectively). The rank order of potencies at the epsilon-nAChR (pancuronium > vecuronium similar mivacurium > rocuronium similar d-tubocurarine > rapacuronium similar Org 9488 > gallamine) correlated highly with the clinical doses needed to produce 50% twitch depression at the adductor pollicis muscle in adults. Neuromuscular blockade by rapacuronium may be enhanced by its metabolite Org 9488. Different drug-receptor affinities of the tested NDMRs contribute to the differences in clinical dose requirements of these drugs needed to achieve appropriate muscle relaxation.

Implications: Potencies of nondepolarizing muscle relaxants, studied at muscle nicotinic acetylcholine receptors expressed in a recombinant expression system, correlate highly with the clinical doses needed in adults to produce 50% twitch depression at the adductor pollicis muscle.