Pugsley M K, Saint D A, Walker M J
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Eur J Pharmacol. 1994 Aug 22;261(3):303-9. doi: 10.1016/0014-2999(94)90121-x.
This study examined the actions of the selective kappa-opioid receptor agonist, U-50,488H, on voltage activated Na+ and K+ currents in isolated rat cardiac myocytes. U-50,488H produced a concentration-dependent block of the transient Na+ current with an ED50 of about 15 microM, and, at higher concentrations (40-50 microM), a block of the plateau K+ current and an increase in the rate of decay of the transient K+ current. In addition U-50,488H produced a hyperpolarising shift in the inactivation curve for the transient Na+ current without altering the voltage dependence for activation and without an effect on the voltage dependence of inactivation or activation of K+ currents. The block of Na+ currents by U-50,488H showed pronounced use dependence. The kappa-opioid receptor antagonist MR2266 did not itself produce any change in the Na+ or K+ currents and did not change the channel blocking properties of U-50,488H. Thus, since the antiarrhythmic actions of U-50,488H are not blocked by MR2266 or naloxone, the effects of U-50,488H to block Na+ and K+ currents are the most likely reasons for its antiarrhythmic actions, rather than an action at kappa-opioid receptors.
本研究检测了选择性κ-阿片受体激动剂U-50,488H对离体大鼠心肌细胞电压激活的Na⁺和K⁺电流的作用。U-50,488H对瞬时Na⁺电流产生浓度依赖性阻滞，半数有效浓度（ED50）约为15μM，且在较高浓度（40 - 50μM）时，对平台期K⁺电流产生阻滞，并使瞬时K⁺电流的衰减速率增加。此外，U-50,488H使瞬时Na⁺电流的失活曲线发生超极化偏移，而不改变激活的电压依赖性，且对K⁺电流的失活或激活的电压依赖性无影响。U-50,488H对Na⁺电流的阻滞表现出明显的使用依赖性。κ-阿片受体拮抗剂MR2266本身对Na⁺或K⁺电流无任何影响，也不改变U-50,488H的通道阻滞特性。因此，由于U-50,488H的抗心律失常作用不受MR2266或纳洛酮的阻断，U-50,488H阻断Na⁺和K⁺电流的作用最有可能是其抗心律失常作用的原因，而非作用于κ-阿片受体。
