Endou M, Tanito Y, Okumura F
Department of Anesthesiology, Yokohama City University School of Medicine, Yokohama, Japan.
J Pharmacol Exp Ther. 1997 Sep;282(3):1480-6.
Bradycardia is one of the inevitable and undesirable responses when the muscle weakness induced by nondepolarizing muscle relaxants is reversed by AChE inhibitors. The current study was designed to compare the bradycardiac effects of the two AChE inhibitors used widely in clinical anesthesia, neostigmine and edrophonium. Isolated, spontaneously beating guinea pig right atrial preparations were used as the experimental model, and in some cases, electrical field stimulation was utilized to stimulate parasympathetic nerve terminals within the atria. Neostigmine decreased the spontaneously beating rate in a concentration-dependent manner at concentrations up to 10 microM. At higher concentrations, the agent restored the beating rate to the predrug control level. Atropine abolished the biphasic response of the atrium to neostigmine. In contrast, edrophonium had no effect on the spontaneous beating rate. However, edrophonium (3 microM) potentiated the field stimulation-induced negative chronotropic effect. Tetrodotoxin did not inhibit the chronotropic effect of neostigmine. Both neostigmine and edrophonium at higher concentrations inhibited the negative chronotropic effect of carbachol. In conclusion, neostigmine possesses potential dual effects on cardiac muscarinic ACh receptors. Low concentrations of neostigmine may stimulate the receptors directly, and at higher concentrations neostigmine may act as an antimuscarinic agent. On the other hand, edrophonium may inhibit the cardiac muscarinic ACh receptors exclusively without stimulating the receptors. These results could at least partially explain the difference between the bradycardiac effects of the agents observed clinically.
当非去极化肌松药所致的肌无力用乙酰胆碱酯酶（AChE）抑制剂逆转时，心动过缓是不可避免且不理想的反应之一。本研究旨在比较临床麻醉中广泛使用的两种AChE抑制剂新斯的明和依酚氯铵的致心动过缓作用。采用离体自发搏动的豚鼠右心房标本作为实验模型，在某些情况下，利用电场刺激来刺激心房内的副交感神经末梢。新斯的明在浓度高达10μM时以浓度依赖性方式降低自发搏动频率。在更高浓度时，该药物可使搏动频率恢复到用药前的对照水平。阿托品消除了心房对新斯的明的双相反应。相比之下，依酚氯铵对自发搏动频率无影响。然而，依酚氯铵（3μM）增强了电场刺激诱导的负性变时作用。河豚毒素不抑制新斯的明的变时作用。新斯的明和依酚氯铵在较高浓度时均抑制卡巴胆碱的负性变时作用。总之，新斯的明对心脏毒蕈碱型ACh受体具有潜在的双重作用。低浓度新斯的明可能直接刺激受体，而在较高浓度时新斯的明可能作为抗毒蕈碱剂起作用。另一方面，依酚氯铵可能仅抑制心脏毒蕈碱型ACh受体而不刺激该受体。这些结果至少可以部分解释临床上观察到的这两种药物致心动过缓作用的差异。
