Hoffmeister H M, Beyer M E, Seipel L
Medizinische Universitätsklinik, Abteilung III, Eberhard-Karls-Universität, Tübingen, Germany.
Am J Cardiol. 1997 Oct 23;80(8A):24G-30G. doi: 10.1016/s0002-9149(97)00711-x.
Besides their proarrhythmic side-effects, most antiarrhythmic drugs exert varying degrees of depressant action on hemodynamics, which may limit their utility, especially in patients with compromised left ventricular function. Antiarrhythmic drugs have not only myocardial inotropic effects but also act on the coronary and peripheral circulation and the heart rate. Thus, sophisticated and appropriate experimental conditions are necessary to define the effect of their direct negative inotropic actions versus their circulatory effects and the impact of drug-induced autonomic modulation. This study describes an extended comparison of amiodarone, d-sotalol, d,l-sotalol, and dofetilide as class III antiarrhythmic drugs with the actions of several class I antiarrhythmic drugs in an open-chest model. The experimental model permits not only measurements in the intact circulation but also measurements of isovolumic indexes of contractility, which are independent of drug-induced changes in ventricular preload and afterload. Furthermore, after autonomic blockade, hemodynamic effects can be measured independently of modulatory adrenergic effects in such a model. d-Sotalol and amiodarone had cardiodepressant effects only at doses significantly higher than the highest doses used clinically. Dofetilide did not have a negative inotropic effect at doses up to 40 ng/kg. However, these results might be modified in experimental models with severely compromised left ventricular function, as was shown for class I antiarrhythmic drugs and for d,l- and d-sotalol. The sensitivity to a drug's negative inotropic action is markedly increased in functionally impaired myocardium. Furthermore, in a model of postischemic myocardial dysfunction, the depressant effect of d-sotalol could largely be avoided by previous autonomic blockade, indicating the importance of the residual beta-blocking potency of d-sotalol in the doses used in our experiments. Thus, in clinically relevant doses amiodarone, d-sotalol, and dofetilide were found to be devoid of negative inotropic actions in the setting of normal left ventricular myocardium. In failing hearts, such effects become more readily evident than they do in normal hearts after high doses of amiodarone and d-sotalol. From beta-blocking experiments in hearts with left ventricular dysfunction, it could be inferred that residual beta-blocking and other negative inotropic mechanisms may produce a net negative inotropic action, thus masking the minor positive class III effects postulated from in vitro experiments. These observations may have significant clinical implications, because they suggest that the intrinsic myocardial effects of antiarrhythmic drugs may be modified by autonomic effects, the status of ventricular function, and changes in preload and afterload.
除了具有致心律失常的副作用外，大多数抗心律失常药物对血流动力学都有不同程度的抑制作用，这可能会限制它们的效用，尤其是在左心室功能受损的患者中。抗心律失常药物不仅具有心肌变力作用，还作用于冠状动脉和外周循环以及心率。因此，需要精密且合适的实验条件来确定其直接负性变力作用与循环效应以及药物诱导的自主神经调节的影响。本研究描述了在开胸模型中，将胺碘酮、d-索他洛尔、d,l-索他洛尔和多非利特这几种Ⅲ类抗心律失常药物与几种Ⅰ类抗心律失常药物的作用进行扩展比较。该实验模型不仅允许在完整循环中进行测量，还能测量与药物诱导的心室前负荷和后负荷变化无关的等容收缩性指标。此外，在自主神经阻滞之后，在此类模型中可以独立于调节性肾上腺素能效应来测量血流动力学效应。d-索他洛尔和胺碘酮仅在剂量显著高于临床使用的最高剂量时才有心脏抑制作用。多非利特在剂量高达40 ng/kg时没有负性变力作用。然而，正如Ⅰ类抗心律失常药物以及d,l-和d-索他洛尔在左心室功能严重受损的实验模型中所显示的那样，这些结果可能会有所改变。在功能受损的心肌中，对药物负性变力作用的敏感性会显著增加。此外，在缺血后心肌功能障碍模型中，通过预先进行自主神经阻滞，很大程度上可以避免d-索他洛尔的抑制作用，这表明在我们实验中所使用剂量的d-索他洛尔的残余β受体阻滞效力的重要性。因此，发现在临床相关剂量下，胺碘酮、d-索他洛尔和多非利特在正常左心室心肌情况下没有负性变力作用。在衰竭心脏中，高剂量的胺碘酮和d-索他洛尔给药后，此类效应比在正常心脏中更容易显现。从左心室功能障碍心脏的β受体阻滞实验可以推断，残余的β受体阻滞和其他负性变力机制可能会产生净负性变力作用，从而掩盖了体外实验推测的轻微Ⅲ类阳性效应。这些观察结果可能具有重要的临床意义，因为它们表明抗心律失常药物的内在心肌效应可能会受到自主神经效应、心室功能状态以及前负荷和后负荷变化的影响。
