Interaction of the neuromuscular blocking drug atracurium with muscarinic acetylcholine receptors.
On isolated rat heart atria, atracurium competitively antagonized the negative chronotropic effect of methylfurmethide, shifting the concentration-response curve to the right without diminishing the agonist's maximal effect; Kd calculated from dose ratios was 3.0 mumol/l. On the longitudinal muscle of rat ileum, atracurium antagonized the effect of methylfurmethide in a non-competitive manner; at 50 mumol/l atracurium, the maximum response to methylfurmethide was diminished by about 50%. Atracurium antagonized the binding of (3H)quinuclidinyl benzilate [3H)QNB) to muscarinic binding sites in the atria, ileal longitudinal muscle and cerebellum with IC50 values of 5-8 mumol/l, and in brain cortex of 25 mumol/l. Atracurium was little efficient, however, in antagonizing the binding of N-(3H-methyl) scopolamine [3H)NMS) to muscarinic binding sites. Complete blockade was not achieved at concentrations up to 1 mmol/l. Concentrations required to diminish the binding by 50% were 10 - 1000 times higher for (3H)NMS than for (3H)QNB. Atracurium brought about the dissociation of (3H)QNB-receptor complexes, but its effect was considerably stronger at a concentration of 30 mumol/l than at 1 mmol/l. Atracurium slowed down the dissociation of (3H)QNB-receptor complexes observed after the addition of atropine. The effects of atracurium on the dissociation of (3H)NMS-receptor complexes were similar to those on (3H)QNB-receptor complexes, but a high concentration of atracurium (1 mmol/l) produced a transient increase in (3H)NMS binding preceding its subsequent dissociation. Although the observations of the antagonism by atracurium of the effect of methylfurmethide on the heart atria, and of the inhibition of the specific binding of (3H)QNB to the atria, ileal smooth muscle, cerebellum and brain cortex are compatible with the assumption of a competitive interaction, the discrepancy between the effects of atracurium on the binding of (3H)QNB and (3H)NMS indicates that atracurium does not bind to the same binding site as (3H)QNB and (3H)NMS. It appears that most effects of atracurium on muscarinic receptors are allosteric and that both negative and positive cooperatives play a role in interactions between atracurium and muscarinic ligands.
Musílková
J
J
Institute of Physiology, Czechoslovak Academy of Sciences, Prague.
Starshinova
L A
LA
Shelkovnikov
S A
SA
Tucek
S
S
D000818:Animals; D001279:Atracurium / Q000378:metabolism*; D001285:Atropine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006325:Heart Atria / Q000378:metabolism; D008297:Male; D009116:Muscarine / Q000031:analogs & derivatives / Q000494:pharmacology; D009130:Muscle, Smooth / Q000378:metabolism / Q000648:ultrastructure; D019832:N-Methylscopolamine; D010276:Parasympatholytics / Q000378:metabolism; D010277:Parasympathomimetics / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011950:Receptors, Cholinergic / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000378:metabolism; D014316:Tritium
D010276:Parasympatholytics; D010277:Parasympathomimetics; D011950:Receptors, Cholinergic; D012602:Scopolamine Derivatives; D014316:Tritium; C008446:5-methylfurtrethonium; D001279:Atracurium; D011813:Quinuclidinyl Benzilate; D001285:Atropine; D009116:Muscarine; D019832:N-Methylscopolamine