Musílková J, Starshinova L A, Shelkovnikov S A, Tucek S
Institute of Physiology, Czechoslovak Academy of Sciences, Prague.
Physiol Res. 1991;40(3):293-304.
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.
在离体大鼠心房肌上，阿曲库铵竞争性拮抗甲呋烟腙的负性变时作用，使浓度 - 效应曲线右移，而不降低激动剂的最大效应；根据剂量比计算的Kd为3.0 μmol/L。在大鼠回肠纵行肌上，阿曲库铵以非竞争性方式拮抗甲呋烟腙的作用；在阿曲库铵浓度为50 μmol/L时，甲呋烟腙的最大反应降低约50%。阿曲库铵拮抗（3H）喹核醇基苯甲酸酯[（3H）QNB]与心房肌、回肠纵行肌和小脑毒蕈碱结合位点的结合，IC50值为5 - 8 μmol/L，在大脑皮质中为25 μmol/L。然而，阿曲库铵拮抗N - （3H - 甲基）东莨菪碱[（3H）NMS]与毒蕈碱结合位点结合的效率很低。在浓度高达1 mmol/L时未实现完全阻断。使（3H）NMS结合减少50%所需的浓度比（3H）QNB高10 - 1000倍。阿曲库铵导致（3H）QNB - 受体复合物解离，但其在30 μmol/L浓度时的作用比在1 mmol/L时强得多。阿曲库铵减慢了加入阿托品后观察到的（3H）QNB - 受体复合物的解离。阿曲库铵对（3H）NMS - 受体复合物解离的作用与对（3H）QNB - 受体复合物的作用相似，但高浓度的阿曲库铵（1 mmol/L）在其随后解离之前使（3H）NMS结合出现短暂增加。尽管观察到阿曲库铵拮抗甲呋烟腙对心房肌作用以及抑制（3H）QNB与心房肌、回肠平滑肌、小脑和大脑皮质特异性结合的现象与竞争性相互作用的假设相符，但阿曲库铵对（3H）QNB和（3H）NMS结合作用的差异表明，阿曲库铵与（3H）QNB和（3H）NMS并非结合于同一结合位点。看来阿曲库铵对毒蕈碱受体的大多数作用是别构性的，并且负性和正性协同作用在阿曲库铵与毒蕈碱配体的相互作用中均起作用。
