Impact of pacing frequency in amiodarone interaction with cardiomyocytes near physiological temperature in health and disease conditions

Abstract

Long QT syndrome type 3 (LQT‐3) is a disease related to abnormal cardiac sodium channel function (Nav 1.5), usually due to augmented late sodium current (INaL), and may lead to ventricular fibrillation. Amiodarone is approved for ventricular fibrillation. Thus, we investigated whether pacing frequency impacts the ability of amiodarone to reverse the arrhythmic phenotype observed in LQT‐3. Anemone neurotoxin 2 (ATX‐II, here named only ATX) was used to enhance INaL in mice left ventricular myocytes (LVM). A video detector system monitored sarcomere shortening. At 1 Hz, amiodarone attenuated sarcomere shortening only at 10 µmol/L; at 3 and 5 Hz, 0.1 and 1 µmol/L amiodarone also reduced sarcomere shortening. However, no effect of amiodarone was observed on time to 50% of sarcomere contraction and relaxation. In LVM exposed to ATX (10 nmol/L), an arrhythmic phenotype was observed, and it was more severe when cells were paced at 1 Hz. Amiodarone failed to reverse the ATX induced phenotype at different pacing frequencies. Thus, our results suggest that amiodarone's ability to reverse arrhythmias induced by augmentation of INaL is limited. These findings suggest further experimentation will be required to clarify whether a clinical effect can be ascribed to an effect of amiodarone on other ion channels in LQT‐3.

Evaluation of right atrium structure and function in a rat model of monocrotaline‐induced pulmonary hypertension: Exploring the possible antiarrhythmic properties of amiodarone

“…However, it is known that amiodarone is a multichannel blocker, with clear action against a variety of ion channel (e.g. calcium and sodium channels) 40,41 and also action against β adrenoceptor and muscarinic receptor 42 . Therefore, the potential in vivo net effect of amiodarone depends on a set of parameters, including: (a) the total plasma concentration of the drug 21 ; (b) the fine balance of ion channels found in the tissue, especially in diseases that alters the expression of a variety of ion channels, as that observed in MCT‐PH rats 6 ; (c) the influence of amiodarone on the ion channel expression after long‐term treatment with the drug 39 ; (d) non‐cardiac effects of the drug 43 ; and (e) unknown factors.…”