Chloroquine terminates stretch-induced atrial fibrillation more effectively than flecainide in the sheep heart.
Chloroquine terminates stretch-induced atrial fibrillation more effectively than flecainide in the sheep heart.
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DOI：
10.1161/circep.111.966820
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发表时间：
2012-06-01
期刊：
影响因子：
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通讯作者：
Jalife J
中科院分区：
文献类型：
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作者：
Filgueiras-Rama D;Martins RP;Mironov S;Yamazaki M;Calvo CJ;Ennis SR;Bandaru K;Noujaim SF;Kalifa J;Berenfeld O;Jalife J
氯喹阻断内向整流钾通道可终止胆碱能房颤患者的折返。然而，内向整流性K+通道和再入是否是维持牵张性房颤(SAF)的重要因素尚不清楚。我们推测，再入是SAF的基础，用氯喹取消再入比用传统的氟卡胺阻断钠通道更有效地终止SAF。30只经朗宁多夫灌流的绵羊心脏暴露于急性和持续的心房牵拉，并进行光学和电学标测。在对照组和氯喹(4μM，N=7)或氟卡胺(2~4μM，N=5)灌流过程中，观察房颤的动态变化。在恢复窦性心律(7/7)前，氯喹增加了转子核心尺寸，降低了再入频率(P<；0.005)，从10.6±0.7 Hz降至6.3±0.7 Hz(p<；7)。氟卡胺对核心大小和折返频率的影响小于氯喹，且不能恢复窦性心律(0/5)。当频率为>；8 Hz时，E-4031(N=7)特异性阻断IKR不能终止房颤。起搏时(N=11)，氟卡胺可逆性降低传导速度(300、250和200ms时约30%，p<；0.05)大于氯喹(11%~19%，周期300、250和200ms，p<；0.05)。只有氯喹在CL300(12%)和250ms(9%)时动作电位时程显著延长(p<；0.05)。氯喹比氟卡胺更有效地终止绵羊离体心SAF，其作用机制是显著增大心脏核心大小，减少心脏折返频率。氯喹的有效性可通过其内向整流性K+通道阻滞谱来解释，并提示再入对维持急性SAF很重要。
Blockade of inward-rectifier K+ channels by chloroquine terminates reentry in cholinergic atrial fibrillation (AF). However, it is unknown whether inward-rectifier K+ channels and reentry are also important in maintaining stretch-induced AF (SAF). We surmised that reentry underlies SAF, and that abolishing reentry with chloroquine terminates SAF more effectively than traditional Na+-channel blockade by flecainide. Thirty Langendorff-perfused sheep hearts were exposed to acute and continuous atrial stretch, and mapped optically and electrically. AF dynamics were studied under control and during perfusion of either chloroquine (4 μM, N=7) or flecainide (2–4 μM, N=5). Chloroquine increased rotor core size and decreased reentry frequency from 10.6±0.7 Hz in control to 6.3±0.7 Hz (p<0.005) just before restoring sinus rhythm (7/7). Flecainide had lesser effects on core size and reentry frequency than chloroquine and did not restore sinus rhythm (0/5). Specific IKr-blockade by E-4031 (N=7) did not terminate AF when frequency values were >8Hz. During pacing (N=11) flecainide reversibly reduced conduction velocity (~30% at cycle length 300, 250 and 200 ms, p<0.05) to a larger extent than chloroquine (11% to 19%, cycle length 300, 250 and 200 ms, p<0.05). Significant action potential duration prolongation was demonstrable only for chloroquine at CL 300 (12%) and 250 ms (9%) (p<0.05). Chloroquine is more effective than flecainide in terminating SAF in isolated-sheep hearts by significantly increasing core size and decreasing reentry frequency. Chloroquine’s effectiveness may be explained by its inward-rectifier K+ channel blockade profile and suggest that reentry is important to maintain acute SAF.