Tetrodotoxin-sensitive Sodium Channels Contribute Significantly To The Cardiac Sodium Current In Dog Ventricles

Abstract

Introduction: The role of the late sodium current (INaL) in hereditary sodium channelopathies such as Long QT syndrome (LQTS), Epilepsy and muscoloskeletal diseases has been well characterized. In most of these cases the sodium channel defect causes an increase in the sustained component of the sodium current, INaL that significantly delays the repolarization of the target cells and tissues action potential. Interestingly, some of these neuronal and skeletal muscle diseases also display a clinical phenotype of prolonged QT interval on the electrocardiogram and cardiac rythm disturbance. These observations combined with others made since the 1970.s indirectly suggest that a tetrodotoxin-sensitive (TTX) component contributes to cardiac INaL.Methods: We investigated the contribution of TTX-sensitive sodium channels (tNaVs) to INaL using patch clamp techniques and selective blockade of the cardiac sodium channel isoform NaV1.5 in dog ventricular myocytes. The thiosulfonate reagent (2-aminoethyl) methanethiosulfonate (MTSEA) binds to a specific cysteine in the pore region of NaV1.5 and selectively blocks this isoform. We looked at the distribution of tNaVs within the epicardial, midmyocardial and endocardial layers of the left venricle myocytes. Our results show that tNaVs contribute up to 40.18 ± 8.30 % of the late sodium current in dog cardiac myocytes. Immunoblot and mRNA data show that the molecular correlates of tNAVs: NaV1.1, NaV1.2 and NaV1.4 account for a significant portion of this contribution.Conclusions: We conclude that tNAVS are present in the cardiac ventricles of higher order mammals. In man, such contribution to INaL could explain the incidence of cardiac arrhythmias and QT prolongation observed in neuronal and musculoskeletal diseases and some of the cardiac secondary effects of neuroleptic drugs.