The mechanism of atrial antiarrhythmic action of RSD1235
The mechanism of atrial antiarrhythmic action of RSD1235
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DOI：
10.1111/j.1540-8167.2005.50028.x
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发表时间：
2005-11-01
影响因子：
2.7
通讯作者：
Beatch, GN
中科院分区：
文献类型：
--
作者：
Fedida, D;Orth, PMR;Beatch, GN
RSD1235的作用机制简介：RSD1235是一种新型的快速、安全的房颤转复药物。(1)在大鼠缺血性心律失常模型上观察其作用机制，并观察其对大鼠心肌细胞动作电位形态的影响。方法和结果：RSD1235的ED50为1.5mU/kg/min，可抑制缺血性心律失常，复极次数增加，但对PR和QRS时程无明显影响。低剂量组大鼠心肌细胞AP延长，高剂量组AP平台升高，AP超射减少。RSD1235对电压门控性K+通道表现出选择性，在hKv1.5(1 Hz)上IC50值为13µM，而在Kv4.2和Kv4.3上分别为38和30 mU M，在HERG通道上为21 mU M。RSD1235对豚鼠心室肌细胞(n=4-5)的I-K_1(IC_(50)=1 mm)和I-Ca、I-L(IC_(50)=220mU/M)均无阻断作用(n=4-5)。该药对NaV1.5呈轻度开放通道阻断(1 Hz时IC50=43µM)，降速后恢复迅速(10-1赫兹，恢复75%，tau=320毫秒)。NaV1.5的阻断效应随着刺激频率的增加而增加，在0.25 Hz时IC50=40mM，在20 Hz时IC50=9mM，在-120 mV时随去极化频率的增加而增加，在-60 mV(1 Hz)时随去极化频率的增加而增加。结论：RSD1235‘S的临床选择性和房颤转复效应源于钾通道的阻断和频率和电压依赖性的I-Na阻断。
Mechanism of Action of RSD1235.Introduction: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients.(1) Its mechanism of action has been investigated in a rat model of ischemic arrhythmia, along with changes in action potential (AP) morphology in isolated rat ventricular myocytes and effects on cloned channels.Methods and Results: Ischemic arrhythmias were inhibited with an ED50 of 1.5 mu mol/kg/min, and repolarization times increased with non-significant effects on PR and QRS durations. AP prolongation was observed in rat myocytes at low doses, with plateau elevation and a reduction in the AP overshoot at higher doses. RSD1235 showed selectivity for voltage-gated K+ channels with IC50 values of 13 mu M on hKv1.5 (1 Hz) versus 38 and 30 mu M on Kv4.2 and Kv4.3, respectively, and 21 mu M on hERG channels. RSD1235 did not block I-K1 (IC50 > 1 mM) nor I-Ca,I-L (IC50= 220 mu M) at 1 Hz in guinea pig ventricular myocytes (n = 4-5). The drug displayed mild (IC50= 43 mu M at 1 Hz) open-channel blockade of Nav1.5 with rapid recovery kinetics after rate reduction (10 -> 1 Hz, 75% recovery with tau= 320 msec). Nav1.5 blocking potency increased with stimulus frequency from an IC50= 40 mu M at 0.25 Hz, to an IC50= 9 mu M at 20 Hz, and with depolarization increasing from 107 mu M at -120 mV to 31 mu M at -60 mV (1 Hz).Conclusions: These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency- and voltage-dependent block of I-Na.