Nanas J N, Mason J W
University of Athens, School of Medicine, Greece.
Circulation. 1995 Jan 15;91(2):451-61. doi: 10.1161/01.cir.91.2.451.
The reason for the delay in onset of the electrophysiological effects and antiarrhythmic efficacy of amiodarone is not clear. The relation between the development of the electrophysiological effects of amiodarone and its myocardial concentration is unknown. We therefore examined the time course of development of electrophysiological effects during intracoronary infusion of amiodarone and related these changes to myocardial concentrations.
Amiodarone (0.139 mg/min) or normal saline was infused for 10 hours into the proximal left anterior descending coronary artery of 24 open-chest dogs. Nineteen animals received intracoronary amiodarone and 5 received normal saline (control group). Ten of the 19 that received amiodarone underwent electrophysiological study (amio-EPS group). Sixteen of the 19, including 7 from the amio-EPS group, underwent pharmacological study (PS group). In the amio-EPS group during pacing at a cycle length of 300 ms, changes in conduction velocities in drug-exposed myocardium referenced to nonexposed myocardium at 1 hour of infusion were -3.7% in the longitudinal direction (P = NS) and -7.2% in the transverse direction (P < .05); at 3 hours, -12.9% (P < .05) and -9.1% (P < .05); and at 9 hours, -32.9% (P < .02) and -31.7% (P < .01). These changes were dependent on amiodarone concentration (R2 = .83). There was also an obvious rate-dependent effect that was more pronounced for transverse conduction velocities. This effect was also dependent on amiodarone concentration. In the PS group, amiodarone levels in the drug-exposed myocardium increased from a mean of 5.95 microgram/g at 15 minutes of infusion to 188.88 microgram/g at the 10th hour. This increase was time dependent (R2 = .91). In the nonexposed myocardium, amiodarone levels were always low and increased minimally over time from a mean of 2.68 to 14.45 microgram/g. This increase was also time dependent (R2 = .97).
Selective intracoronary amiodarone infusion resulted in selective drug accumulation and concomitant time-dependent reduction of myocardial conduction velocity. There was a significant correlation between the extent of reduction of conduction velocity and myocardial amiodarone concentration but not coronary arterial or systemic concentration. Repolarization was not significantly altered.
胺碘酮电生理效应及抗心律失常疗效出现延迟的原因尚不清楚。胺碘酮电生理效应的产生与其心肌浓度之间的关系也不明确。因此，我们研究了冠状动脉内输注胺碘酮期间电生理效应的发展时间进程，并将这些变化与心肌浓度相关联。
对24只开胸犬的左前降支冠状动脉近端输注胺碘酮（0.139mg/min）或生理盐水，持续10小时。19只动物接受冠状动脉内胺碘酮输注，5只接受生理盐水（对照组）。接受胺碘酮输注的19只动物中，10只进行了电生理研究（胺碘酮-电生理研究组）。19只中的16只，包括胺碘酮-电生理研究组中的7只，进行了药理学研究（药理学研究组）。在胺碘酮-电生理研究组中，以300ms的周期长度起搏时，输注1小时后，与未暴露心肌相比，药物暴露心肌的纵向传导速度变化为-3.7%（P=无显著性差异），横向传导速度变化为-7.2%（P<.05）；3小时时，分别为-12.9%（P<.05）和-9.1%（P<.05）；9小时时，分别为-32.9%（P<.02）和-31.7%（P<.01）。这些变化取决于胺碘酮浓度（R2=.83）。还存在明显的频率依赖性效应，对横向传导速度更为明显。这种效应也取决于胺碘酮浓度。在药理学研究组中，药物暴露心肌中的胺碘酮水平从输注15分钟时的平均5.95μg/g增加到第10小时的188.88μg/g。这种增加是时间依赖性的（R2=.91）。在未暴露心肌中，胺碘酮水平始终较低，随时间从平均2.68μg/g微升至14.45μg/g。这种增加也是时间依赖性的（R2=.97）。
选择性冠状动脉内输注胺碘酮导致药物选择性蓄积，并伴随心肌传导速度随时间的降低。传导速度降低的程度与心肌胺碘酮浓度之间存在显著相关性，但与冠状动脉或全身浓度无关。复极化未发生显著改变。
