Padrini R, Speranza G, Nollo G, Bova S, Piovan D, Antolini R, Ferrari M
Department of Pharmacology, University of Padova, Italy.
Pharmacol Res. 1997 May;35(5):409-16. doi: 10.1006/phrs.1997.0152.
The inadequacy of the QT interval to shorten following heart rate increase is a feature of the inherited long QT syndrome and may have a role in the genesis of the typical arrhythmias associated with this syndrome (torsade des pointes). The aim of our study was to evaluate whether drugs that prolong the QT interval, such as amiodarone and D-sotalol, may also impair the ability of the QT interval to adapt to sudden heart rate changes. Experiments were carried out on isolated perfused guinea pig hearts (Langendorff preparation). Driving frequency was changed, in steps, every two minutes (Hz: 2.5-3-2.5-3.75-2.5-5-2.5), while epicardial ECG was continuously recorded on magnetic tape. QT interval was automatically measured by means of a beat-by-beat analysis program. D-sotalol was added to the perfusion medium at a concentration of 4 micrograms ml-1, while amiodarone was administered, before in vitro evaluation, for seven days (50 mg kg-1 per day, intraperitoneally). In control experiments two phases of QT adaptation were identified: an abrupt QT shortening at the first beat after frequency change (QT1), followed by a gradual, exponential QT shortening that reached a new steady state in about 1 min (half life: 13 sec). The electrical restitution curve (the relation between QT1 and the corresponding diastolic interval) had a rate constant of 57 +/- 8 ms. Neither drug changed the slow component of QT adaptation. However, both drugs increased the ability of QT to shorten upon premature stimulation: D-sotalol by increasing the rate constant of the restitution curve and amiodarone by decreasing the y-intercept. Our results indicate that D-sotalol and amiodarone do not impair QT shortening during tachycardia but, on the contrary, they may favour QT adaptation, thus reducing the likelihood of the potentially lethal 'R on T phenomenon'. This may be an additional mechanism by which these drugs can exert their antifibrillatory action.
心率增加后QT间期缩短不足是遗传性长QT综合征的一个特征，可能在与该综合征相关的典型心律失常（尖端扭转型室速）的发生中起作用。我们研究的目的是评估延长QT间期的药物，如胺碘酮和D - 索他洛尔，是否也会损害QT间期适应心率突然变化的能力。实验在离体灌注豚鼠心脏（Langendorff制备）上进行。每隔两分钟逐步改变驱动频率（Hz：2.5 - 3 - 2.5 - 3.75 - 2.5 - 5 - 2.5），同时将心外膜心电图连续记录在磁带上。QT间期通过逐搏分析程序自动测量。将D - 索他洛尔以4微克/毫升的浓度加入灌注培养基中，而胺碘酮在体外评估前连续七天（每天50毫克/千克，腹腔注射）给药。在对照实验中，确定了QT适应的两个阶段：频率改变后第一搏时QT突然缩短（QT1），随后是逐渐的、指数性的QT缩短，约1分钟后达到新的稳态（半衰期：13秒）。电恢复曲线（QT1与相应舒张期的关系）的速率常数为57±8毫秒。两种药物均未改变QT适应的慢成分。然而，两种药物都增加了QT在早搏刺激时缩短的能力：D - 索他洛尔通过增加恢复曲线的速率常数，胺碘酮通过降低y轴截距。我们的结果表明，D - 索他洛尔和胺碘酮在心动过速期间不会损害QT缩短，相反，它们可能有利于QT适应，从而降低潜在致命的“R波落在T波上现象”的可能性。这可能是这些药物发挥抗纤颤作用的另一种机制。
