title: Isobolographic analysis of non-depolarising muscle relaxant interactions at their receptor site.
abstract: Administration of certain combinations of non-depolarising muscle relaxants produces greater than expected neuromuscular blockade. Synergistic effects may be explained by drug interactions with the postsynaptic muscle nicotinic acetylcholine receptor. To investigate this hypothesis, the adult mouse muscle nicotinic acetylcholine receptor (alpha(2)beta delta epsilon) was heterologously expressed in Xenopus laevis oocytes and activated by the application of acetylcholine (10 microM). The effects of five individually applied muscle relaxants and six combinations of structurally similar and dissimilar compounds were studied. Drug combinations containing equipotent concentrations of two agents were tested and dose-response curves were determined. All compounds tested alone and in combination produced rapid and readily reversible, concentration-dependent inhibition. Isobolographic and fractional analyses indicated additive interactions for all six tested combinations. These findings suggest that synergistic neuromuscular blocking effects, observed for the administration of certain combinations of muscle relaxants, do not result from purely postsynaptic binding events at the muscle nicotinic acetylcholine receptor, but rather from differential actions on pre- and postsynaptic sites.
authors.affiliation: Department of Anaesthesia and Perioperative Care, University of California, 513 Parnassus Avenue, Box 0542, San Francisco, CA 94143-0542, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Paul
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Kindler
authors.forename: Ralf M
authors.initials: RM
authors.lastname: Fokt
authors.forename: Natalie C J
authors.initials: NC
authors.lastname: Dipp
authors.forename: C Spencer
authors.initials: CS
authors.lastname: Yost
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004594:Electrophysiology; D005260:Female; D005703:Gallamine Triethiodide / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D000077590:Mivacurium; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010197:Pancuronium / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014403:Tubocurarine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014673:Vecuronium Bromide / Q000494:pharmacology; D014981:Xenopus
chemical_list: D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014665:Vasodilator Agents; D000077590:Mivacurium; D014673:Vecuronium Bromide; D010197:Pancuronium; D000109:Acetylcholine; D005703:Gallamine Triethiodide; D014403:Tubocurarine