Pharmaco-Electrophysiology of Isolated Perfused Rat Heart Assessed with Flexible Microelectrode Arrays

Background: Heart slices and enzymatically dissociated cardiomyocytes are used in cardiac safety pharmacology for extracellular recording using microelectrode array (MEA). The aim of this study was to set up and validate a vitro cardiac surface mapping system for studies pharmaco-electrophysiology effects in Langendorff perfused rat hearts by flexible MEA. Materials and Methods: Hearts isolated from Sprague-Dawley (SD) male rat of either sex weighing 200-250 g were perfused by the Langendorff method with Tyrode’s solution. A cardiac surface mapping system suitable for recordings from Langendorff-perfused rat hearts using the Class III antiarrhythmic agents has been developed. In 48 Langendorff-perfused rat hearts, after obtaining baseline data, ibutilide, amiodarone or dofetilide were infused. The field potentials (FP) and heart rhythm by Multi-channel flexible MEA were monitored throughout the experiments. Results: Langendorff perfusion enabled the autorhythmicity of the rats’ heart last about 240 min. Simultaneous 64 channels FP graphs could be recorded stably. FP duration revealed significant, dose-dependent prolongation more than 2 fold upon administration of three drugs, but present a different proarrhythmic properties (dofetilide> ibutilide>amiodarone). Dofetilide and ibutilide lead to early afterdepolarizations (EAD) and ventricular tachycardia (VT) but not amiodarone. Amiodarone led to atrial ventricular block, atrial flutter and junctional escape rhythm, in the presence of ibutilide or dofetilide, neither EAD nor VT occur. Conclusion: Our model with isolated rat heart and flexible MEA represents a novel and reliable tool for application in cardiac safety pharmacology and preclinical studies of electrophysiological effects of various pathophysiological concepts.